Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1 -- 4685 2022-08-12 14:59:36 |
2 format corrected. + 311 word(s) 4996 2022-08-15 06:17:43 | |
3 format corrected. + 2 word(s) 4998 2022-08-15 07:50:24 | |
4 format corrected. Meta information modification 4998 2022-08-15 07:53:34 | |
5 We have reported the correlations between PDAC and the three main metabolic pathways. -2478 word(s) 2520 2022-08-23 11:23:40 | |
6 Typos corrected. Meta information modification 2520 2022-08-30 09:55:49 |

Video Upload Options

Do you have a full video?

Confirm

Are you sure to Delete?
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Ali, A.;  Chianese, U.;  Papulino, C.;  Toraldo, A.;  Abakar, M.E.A.;  Passaro, E.;  Cennamo, R.;  Gaudio, N.D.;  Altucci, L.;  Benedetti, R. Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/26108 (accessed on 20 June 2024).
Ali A,  Chianese U,  Papulino C,  Toraldo A,  Abakar MEA,  Passaro E, et al. Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/26108. Accessed June 20, 2024.
Ali, Ahmad, Ugo Chianese, Chiara Papulino, Antonella Toraldo, Mawada Elmagboul Abdalla Abakar, Eugenia Passaro, Rosario Cennamo, Nunzio Del Gaudio, Lucia Altucci, Rosaria Benedetti. "Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma" Encyclopedia, https://encyclopedia.pub/entry/26108 (accessed June 20, 2024).
Ali, A.,  Chianese, U.,  Papulino, C.,  Toraldo, A.,  Abakar, M.E.A.,  Passaro, E.,  Cennamo, R.,  Gaudio, N.D.,  Altucci, L., & Benedetti, R. (2022, August 12). Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma. In Encyclopedia. https://encyclopedia.pub/entry/26108
Ali, Ahmad, et al. "Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma." Encyclopedia. Web. 12 August, 2022.
Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma
Edit

Metabolism plays a fundamental role in both human physiology and pathology, including pancreatic ductal adenocarcinoma (PDAC) and other tumors. Anabolic and catabolic processes do not only have energetic implications but are tightly associated with other cellular activities, such as DNA duplication, redox reactions, and cell homeostasis. PDAC displays a marked metabolic phenotype and the observed reduction in tumor growth induced by calorie restriction with in vivo models supports the crucial role of metabolism in this cancer type. The aggressiveness of PDAC might, therefore, be reduced by interventions on bioenergetic circuits. 

PDAC metabolism glucose amino acids lipids

1. Activation and Maintenance of Glycoltyc Flux

In PDAC, the expression of glycolytic genes is regulated at both transcriptional and post-transcriptional level via oncogenic KRAS [1]. KRAS signaling plays a crucial role in regulating transcription of both glucose transporters (GLUTs) and key glycolysis genes [2]. Glucose need of the PDAC system seems to be due to the expression of facilitated GLUTS and sodium-glucose transporter (SGLTs); PDAC tumors showed both increased pyruvate carboxylation and glucose oxidation via pyruvate dehydrogenase in vivo [3]. PDAC progression is induced by the activation of mutant KRAS, resulting in an increase in GLUTs, such as GLUT-1, from low- to high-grade dysplasia. Oxygen is related to GLUT-1 expression through hypoxia inducible factor 1 alpha (HIF-1α). In patients with low expression levels of GLUT-1, neoadjuvant chemotherapy such as TS-1 showed better therapeutic response and better prognosis than in those with higher GLUT-1 expression levels [4]. PDAC tumor biology relies on hypoxia and HIF1α signaling to control tumor-promoting stromal programs, which facilitate progression and tumor cell invasivenes [5]. Hypoxia-activated stromal cells contribute to the invasive growth of PDAC cells by releasing soluble proteins, such as MMP10, and enhance the levels of inflammatory and angiogenetic factors including IL1α, TIE family members, and VEGF-A. MMP10, the main stromal protein driving EMT in tumor cells [6], is reported as a stellate cell product [7], [8]. IL1α was shown to be released by both stromal cells and PDAC cells, thus promoting tumor growth [9] in an autocrine manner [10], and stimulated the fibrotic component [11]. TIE1 upregulation and increased TIE2 transcription in hypoxic stellate cells are crucial for the remodeling and maturation of tumor vasculature [12], forming a complex with angiopoietins and sustaining TIE2 signaling in contacting cells [13]. Altered levels of VEGF-A found in PDAC indicate an imbalance in normal angiogenetic processes [14]. In particular, the high extracellular matrix component associated with vasculature collapse resulted in an increased hypoxic environment, partly explaining the low efficacy of antiangiogenic drugs in this cancer [15] and the inefficient delivery of chemotherapeutic agents [16]. Thus emphasizing a recently described stroma-targeting therapy that aims to reduce the stromal component to improve target achievement [17]. According to the transcriptomic profiles of PDAC patients, ubiquitin specific peptidase 25 (USP25) depletion was linked to decreased levels of HIF-1α, GLUT-1, and glycolysis signaling. This suggests that USP25 complex deubiquitinates and stabilizes the HIF-1 α transcription factor from a mechanistic point of view [18]. SGLTs also play a functional role in glucose uptake, since the selective inhibition of SGLT2 in mouse models of pancreatic cancers led to a decrease in glucose uptake [19]. Furthermore, the hypoxic environment is essential for maximizing energy yield and biomass production, which are ensured by the lack of oxygen, which promotes conversion of pyruvate into lactate by Lactate Dehydrogenase A [20]. In such way, ATP is generated and an increased amount of lactic acid is released outside of the cell, acidifying the microenvironment and in turn facilitating PDAC progression [21]. Monocarboxylate transporters (MCTs), which transport lactate, are abundantly expressed in PDAC [22]. MCT1 and MCT4 regulate lactate efflux through KRAS-dependent signaling, releasing intracellular accumulated lactate and maintaining intracellular pH [23]. This process facilitates the oxidation of nicotinamide adenine dinucleotide (NADH) to NAD+, a cofactor for oxidizing glyceraldehyde 3-phosphate and driving glycolysis [24]. The glycolytic shift meets the energy demands required for tumor growth, as well as supplying the building blocks for biochemical reactions and intermediates [25]. MUC1 and MUC13 transporters also stabilize transcription of HIF-1α during hypoxia conditions and induce the expression of glycolytic genes [26] associated with poor survival rates in PDAC patients [18]. In contrast, CD147 works as a chaperone for the membrane localization of MCT1 and MCT4, both expressed in PDAC cells [27]. Whether the interaction between CD147 and MCT is related to PDAC progression has not yet been determined [28]; however, depletion of MCT4 reduces cell viability, whereas depletion of CD147 affects tumor growth in xenograft models [23], [29]. As regards the glycolytic flux of anabolic pathways in PDAC, the pentose phosphate pathway (PPP) is a branch of glycolysis that directs glucose flux to oxidation and regulates NADP and nucleic acid synthesis, which ensure fatty acid (FA) production and cell survival under stress conditions [30]. According to a metabolomic analysis of PDAC, the adaptation to acidosis status increases glucose and decreases glycolysis, driving a shift to PPP [31], [21]. PPP occurs in two different ways: oxidatively and non-oxidatively. The oxidative arm transforms glucose 6-phosphate into ribulose-5-phosphate and CO2, which are essential for maintaining redox equilibrium under stress conditions [32]. The non-oxidative branch produces glycolytic intermediates, resulting in the production of sugar phosphate, an important precursor for amino acid synthesis, ribose-5-phosphate which is needed for nucleic acid synthesis [33]. Furthermore, oncogenic KRAS selectively activates non-oxidative PPP, possibly via the induction of genes involved in the non-oxidative arm, such as ribulose-5-phosphate isomerase (RPIA) [34]. Low expression levels of RPIA deficits result in reduced KRAS-driven signaling in PDAC cells, indicating the importance of non-oxidative PPP in metabolic function [1]. Growing evidence suggests that non-oxidative PPP contributes to gemcitabine resistance in PDAC and that reduced expression of transketolase is associated with higher gemcitabine sensitivity in PDAC patients, strengthening the therapeutic potential of targeting non-oxidative PPP [26]. Post-transcriptional processes, such as those modulated by microRNAs, are also thought to play an important role in PDAC progression [35]. microRNAs are linked to the regulation of glycolysis in PDAC; the tumor suppressor miR-124 regulates MCT1 [36], resulting in increased intracellular pH that reduced acidic environment and decreased PANC-1 cell proliferation. miR-135 was found significantly overexpressed in PDAC patient samples compared to normal tissue, and notably associated to a metabolic alteration. It has been observed miR-135 accumulation during glutamine deprivation, promoted by mutant TP53. Specifically, miR-135 targets phosphofructokinase-1 inhibiting aerobic glycolysis and promoting TCA cycle [35]. Some studies have already been conducted on the potential role of mirna as biomarkers of PDAC. miRNA-483-3p and miRNA-21 were found to be significantly higher from blood plasma in PDAC compared to healthy controls, and related to to advanced stage disease [37], [38]. Further functional studies on miR-124 may lead to new therapeutic strategies for PDAC [36].

2. Amino Acids as an External Energy Resource

The PDAC phenotype is also triggered by the rewiring of amino acids, contributing to the metabolic profile of PDAC by regulating cell proliferation, invasion, and redox homeostasis [39]. In cellular hemostasis, glutamine is a multifunctional amino acid that serves as a key energy source [40]. The biological activities of glutamine rangefrom providing energy to stabilizing reducing agents, contributing to the biosynthesis of purines and pyrimidines, and its involvement in PDAC has been recognized [41], [42]. PDAC cells can compensate for the increased metabolic demand either by increasing glutamine production or by increasing glutamine uptake from the environment, thus reducing glutamine levels in blood serum despite the abundance of fibrotic cells in the pancreas [43]. Glutamate-Ammonia Ligase (GLUL), the enzyme responsible for de novo production of glutamine, was found elevated in PDAC [44]. Although the cause of this increase is not completely clear, CRISPR/Cas9 ablation of GLUL in PDAC mouse models reduced tumor growth [44]. Metabolic niches also contribute significantly to cancer development and progression. Autophagy plays a pivotal role in supporting the growth of PDAC through fibroblasts [45]. Autophagy allows fibroblasts to break down misfolded proteins and ECM, releasing large quantities of amino acids into the microenvironment [46]. In addition, circulating macromolecules enter PDAC cells using using the Na+-dependent glutamine transporter SLC1A5, in the case of glutammine, or via macropinocytosis/micropinocytosis, for proteins, a mechanism linked to the growth of cancer cells expressing oncogenic KRAS [47], [48], [49], [50]. Micropinocytosis inhibitors were found to interfere with this ability in MIAPaCa2 cells, a PDAC model [51]. Glutamine intake is converted into glutamate to feed a complex network of enzymes and intermediates. PDAC utilizes glutamate to activate the tricarboxylic acid (TCA) cycle and electron transport chain after its conversion into alpha-ketoglutarate (αKG) in mitochondria; notably, αKG acts as an epigenetic factor [52]. αKG may also function in a TCA-independent manner by acting as a cofactor for dioxygenases, controlling gene expression, DNA methylation, and DNA damage reactivity [53]. Similarly to glutamine, alanine is also required for metabolic homeostasis in PDAC and is derived from pancreatic stellate cells (PSCs) [54]. Several studies have investigated the unidirectional channeling of alanine between PSCs and PDAC [54], [55]. SLC38A2 activity facilitates alanine uptake, although other transporters have been identified, including SLC1A4 [54]. PDAC cells also express the mitochondrial isoform of glutamic-pyruvic transaminase ALT2 for de novo synthesis and alanine utilization. The ratio between aspartate transaminase AST and alanine aminotransferase ALT was used to predict poor prognosis and response to gemcitabine/nab-paclitaxel treatment in PDAC patients [56]. In co- injection xenograft models, the beneficial support provided by stellate cells was disrupted by targeting SLC38A2, causing significant tumor regression in PDAC and affecting cytosolic alanine internalization and concentration [54]. PDAC can also use proline as a fuel source, and this energy comes from collagen that is largely found in the ECM [57]. Proline degradation by the mitochondrial enzyme PRODH1 plays as an active factor in PDAC cell proliferation both in vitro and in vivo [57], indicating that ECM is an important nutrient reservoir for cancer cell metabolic flexibility. Some context-specific metabolic mechanisms have also been described for PDAC, such as the TP53-mediated overexpression of SLC1A3, an Na+/K+/H+-dependent aspartate/glutamate transporter, which enables the aspartate metabolism to maintain cancer cell survival and tumor growth under conditions of glutamine starvation [58]. By perturbing glutamine metabolism, redox homeostasis proteins are deregulated, leading to reactive oxygen species ROS accumulation, which then leads to a cellular redox imbalance facilitating PDAC cell apoptosis [59]. Pharmacological and genetic targeting of nicotinamide phosphoribosyltransferase (Nampt), a key redox enzyme, inhibited cell growth and survival of PDAC cells in vitro and in vivo [60]. Other findings link amino acids with cell fate. KRAS-driven PDAC mouse models was less responsive to depletion of serine and glycine [61]. Cysteine depletion induced ferroptosis in KRAS/TP53 mutant pancreatic tumors in mice, and the disruption of amino acid pathways was able to enhance gemcitabine chemosensitivity in drug-resistant PDAC [62], [59]. Ferroptotic damage can result in the of release damage-associated molecular pattern molecules, which can lead to inflammation [63]

3. Fatty Acids Contribute to PDAC Progression

Epidemiological studies correlated PDAC with dyslipidemia [64], showing an altered biosynthesis of cholesterol and other lipids in murine PDAC cells [65], [66], [67], [68]. Lipogenic enzymes are frequently overexpressed in PDAC, supporting their potential contribution to tumor growth [69]. Alanine from PSCs can be taken up by PDAC cells and used for FA biosynthesis. Serum FA synthase (FASN) levels are in fact generally higher in PDAC patients [70] as a result of SREBP1 activity [71] and are associated with lower survival than in patients with low FASN expression and with poor response to gemcitabine [72], [73]. Once again, driver mutations in KRAS and loss-of-function in TP53 reprogram metabolism, accelerating cholesterol biosynthesis and uptake [1], mediating metabolic plasticity via SREBP1-dependent regulation of transforming growth factor-β expression involved in PDAC differentiation. Oncogenic KRAS regulates hormone-sensitive lipase (HSL) to control metabolism by regulating lipid storage and utilization (specifically through suppression of HSL expression), leading to lipid droplet (LD) accumulation and priming tumor cells for invasion [74]. Perilipins constitute the major proteins resident on LD surface controlling intracellular lipid homeostasis [75], [76]. Perilipin 2 (PLIN2) was found overexpressed in a cohort of 181 PDAC patients [77] and was associated with poor MFS, DFS, and OS rates as well as with poor prognosis. Further investigations using an in vivo mouse model showed that exposure of pancreatic β cells to fatty acids stimulated PLIN2 expression, impacting on cellular stress, whereas its ablation prevented fatty acid-induced TG accumulation [76], mitigating stress and leading to a significant improvement of hyperglycemia [78]. Notably, PLIN2 is expressed in other cell types such as monocytes and macrophages [79], where its expression was positively correlated with LGALS9 in PDAC; this protein converts polarized macrophages into an M2 phenotype, leading to the inhibited secretion of T cell cytokines [80]. These findings suggest that PLIN2 might participate in immunomodulatory effects by regulating tumor-associated macrophages in the tumor microenvironment [81]. A high fat diet was able to ameliorate mutated Kras activity, increasing fibrosis and enhancing PDAC progression in a mouse model [82], and a recent study with in vivo mouse model showed a causal and positive corrrelation between obesity and early PDAC progression, identifying altered beta cell expression of cholecystokinin (Cck) in response to obesity defining islet Cck as a promoter in oncogenic Kras-driven PDAC [83]. LDs are recognized as important regulators in cancer; these dynamic intracellular organelles are used for cellular storage of lipids such as triacylglycerol and cholesterol ester [84]. Lipids can thus be catabolized by lipolysis via lipases to liberate free FAs [85], causing increased FA oxidation and oxidative metabolism, which drives tumor cell invasion. Low-density lipoprotein receptor (LDL-R) is highly expressed in PDAC and is associated with increased PDAC recurrence [86]. LDL-R increases cholesterol uptake, while its inhibition reduces proliferation, affecting ERK1/2 survival pathway, and sensitizes PDAC cells to chemotherapeutic drugs, favoring tumor regression [86]. Interestingly, mutated KRAS is able to control the sequestration of extracellular unsaturated FAs [87]. ACSL3 activity, a protein coding gene for a member of Acyl-CoA synthetase long chain family, has been linked to KRAS-mutated tumors [88] and associated with the retention of extracellular unsaturated FAs by converting them into esters that remain confined in PDAC cells [89], [90]. Serum lipid depletion or ACSL3 inhibition decreased tumor cell proliferation, provoking a rebound effect due to lipid restriction that was balanced by increased autophagic flux, in both in vitro and in vivo models [91]. Notably, combining lipid depletion with autophagy inhibitors induced the most potent effect, with arrest of PDAC proliferation and increased apoptosis [91]. Recently, metabolomic profiles clarified key aspects of the metabolic signature of pancreatic cancer stem cells (PCSCs) originating from PDAC cells, revealing a fundamental role for pyruvate-malate cycle and lipid metabolism in their survival [92]. While lipidomic analysis suggested a strong induction of long chain FAs and accumulation of LDs mediated by ELOVL5, a fatty acid elongase, other data highlighted cardiolipin acyl-chain composition as pivotal in PCSCs [93]. Changes in cardiolipin composition have an impact on enzymes involved in the respiratory process and integrity of the inner membrane [94], [95], indicating that cardiolipin plays a critical role in oxidative phosphorylation. A comprehensive investigation on serum lipids of 830 PDAC samples by mass spectrometric determination revealed statistically significant differences between PDAC patients and healthy controls [96]. While a lysophosphatidylcholine LPC 18:2 was positively correlated with survival, Cer 36:1, Cer 38:1, Cer 42:2, PC 32:0, PC O-38:5, and SM 42:2 were inversely correlated, suggesting their potential role as prognostic biomarkers. Other data in PDAC tissues by MALDI-MSI analyses indicated that LPC (16:0, 18:1), as reported for other LPCs [97], [98], and DAG 36:2 were decreased, while PC 32:0, SM d36:1, and SM d42:3 were increased [99]. Glycerophospholipid and sphingolipid metabolism pathways were also found dysregulated in PDAC [99]. About lipid saturation degree, polyunsaturated phosphatidylcholines were reduced in serum of PDAC [100] it is tempting to speculate that this altered profile might reflect apoptotic resistance in PDAC, given that polyunsaturated FAs, via peroxidation, act as substrates for ferroptosis in cell membranes [101][102].

References

  1. Haoqiang Ying; Alec C. Kimmelman; Costas A. Lyssiotis; Sujun Hua; Gerald C. Chu; Eliot Fletcher-Sananikone; Jason W. Locasale; Jaekyoung Son; Hailei Zhang; Jonathan L. Coloff; et al.Haiyan YanWei WangShujuan ChenAndrea VialeHongwu ZhengJi-Hye PaikCarol LimAlexander R. GuimaraesEric S. MartinJeffery ChangAram F. HezelSamuel R. PerryJian HuBoyi GanYonghong XiaoJohn M. AsaraRalph WeisslederY. Alan WangLynda ChinLewis C. CantleyRonald A. DePinho Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism. Cell 2012, 149, 656-670, 10.1016/j.cell.2012.01.058.
  2. Jihye Yun; Carlo Rago; Ian Cheong; Ray Pagliarini; Philipp Angenendt; Harith Rajagopalan; Kerstin Schmidt; James K. V. Willson; Sandy Markowitz; Shibin Zhou; et al.Luis A. DiazVictor E. VelculescuChristoph LengauerKenneth W. KinzlerBert VogelsteinNickolas Papadopoulos Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells. Science 2009, 325, 1555-1559, 10.1126/science.1174229.
  3. Allison N Lau; Zhaoqi Li; Laura V Danai; Anna M Westermark; Alicia M Darnell; Raphael Ferreira; Vasilena Gocheva; Sharanya Sivanand; Evan C Lien; Kiera M Sapp; et al.Jared R MayersGiulia BiffiChristopher R ChinShawn M DavidsonDavid A TuvesonTyler JacksNicholas J MathesonOmer YilmazMatthew G Vander Heiden Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma. eLife 2020, 9, 234-239, 10.7554/elife.56782.
  4. Hiroshi Kurahara; Kosei Maemura; Yuko Mataki; Masahiko Sakoda; Satoshi Iino; Yota Kawasaki; Takaaki Arigami; Shinichiro Mori; Yuko Kijima; Shinichi Ueno; et al.Hiroyuki ShinchiShoji Natsugoe Significance of Glucose Transporter Type 1 (GLUT-1) Expression in the Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma. Annals of Surgical Oncology 2018, 25, 1432-1439, 10.1245/s10434-018-6357-1.
  5. Kinga B. Stopa; Agnieszka A. Kusiak; Mateusz D. Szopa; Pawel E. Ferdek; Monika A. Jakubowska; Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies. International Journal of Molecular Sciences 2020, 21, 3218, 10.3390/ijms21093218.
  6. Thomas R. Cox; The matrix in cancer. Nature Cancer 2021, 21, 217-238, 10.1038/s41568-020-00329-7.
  7. Minoti V. Apte; Jeremy S. Wilson; Aurelia Lugea; Stephen J. Pandol; A Starring Role for Stellate Cells in the Pancreatic Cancer Microenvironment. Gastroenterology 2013, 144, 1210-1219, 10.1053/j.gastro.2012.11.037.
  8. M Sinn; Carsten Denkert; J K Striefler; U Pelzer; J M Stieler; M Bahra; P Lohneis; B Dörken; H Oettle; H Riess; et al.B V Sinn α-Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001 study. British Journal of Cancer 2014, 111, 1917-1923, 10.1038/bjc.2014.495.
  9. Vegard Tjomsland; Anna Spångeus; Johanna Välilä; Per Sandström; Kurt Borch; Henrik Druid; Sture Falkmer; Ursula Falkmer; Davorka Messmer; Marie Larsson; et al. Interleukin 1α Sustains the Expression of Inflammatory Factors in Human Pancreatic Cancer Microenvironment by Targeting Cancer-Associated Fibroblasts. Neoplasia 2011, 13, 664-IN3, 10.1593/neo.11332.
  10. Zhuonan Zhuang; Huai-Qiang Ju; Mitzi Aguilar; Takashi Gocho; Hao Li; Tomonori Iida; Harold Lee; Xiaoqiang Fan; Haijun Zhou; Jianhua Ling; et al.Zhongkui LiJie FuMin WuMin LiDavide MelisiYoichiro IwakuraKesen XuJason B. FlemingPaul J. Chiao IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-κB Activation. Clinical Cancer Research 2016, 22, 1432-1444, 10.1158/1078-0432.ccr-14-3382.
  11. Giulia Biffi; Tobiloba E. Oni; Benjamin Spielman; Yuan Hao; Ela Elyada; Youngkyu Park; Jonathan Preall; David A. Tuveson; IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma. Cancer Discovery 2019, 9, 282-301, 10.1158/2159-8290.cd-18-0710.
  12. Veli-Matti Leppänen; Pipsa Saharinen; Kari Alitalo; Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization. Proceedings of the National Academy of Sciences 2017, 114, 4376-4381, 10.1073/pnas.1616166114.
  13. Emilia A. Korhonen; Anita Lampinen; Hemant Giri; Andrey Anisimov; Minah Kim; Breanna Allen; Shentong Fang; Gabriela D’Amico; Tuomas J. Sipilä; Marja Lohela; et al.Tomas StrandinAntti VaheriSeppo Ylä-HerttualaGou Young KohDonald M. McDonaldKari AlitaloPipsa Saharinen Tie1 controls angiopoietin function in vascular remodeling and inflammation. Journal of Clinical Investigation 2016, 126, 3495-3510, 10.1172/jci84923.
  14. Masahiro Inoue; Jeffrey H Hager; Napoleone Ferrara; Hans-Peter Gerber; Douglas Hanahan; VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic β cell carcinogenesis. Cancer Cell 2002, 1, 193-202, 10.1016/s1535-6108(02)00031-4.
  15. Vito Longo; Oronzo Brunetti; Antonio Gnoni; Stefano Cascinu; Giampietro Gasparini; Vito Lorusso; Domenico Ribatti; Nicola Silvestris; Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue. Oncotarget 2016, 7, 58649-58658, 10.18632/oncotarget.10765.
  16. Panagiotis Sarantis; Evangelos Koustas; Adriana Papadimitropoulou; Athanasios G Papavassiliou; Michalis V Karamouzis; Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World Journal of Gastrointestinal Oncology 2020, 12, 173-181, 10.4251/wjgo.v12.i2.173.
  17. Bolun Jiang; Li Zhou; Jun Lu; Yizhi Wang; Chengxi Liu; Lei You; Junchao Guo; Stroma-Targeting Therapy in Pancreatic Cancer: One Coin With Two Sides?. Frontiers in Oncology 2020, 10, 576399, 10.3389/fonc.2020.576399.
  18. Jessica K. Nelson; May Zaw Thin; Theodore Evan; Steven Howell; Mary Wu; Bruna Almeida; Nathalie Legrave; Duco S. Koenis; Gabriela Koifman; Yoichiro Sugimoto; et al.Miriam Llorian SopenaJames MacRaeEmma NyeMichael HowellAmbrosius P. SnijdersAndreas PrachaliasYoh ZenDebashis SarkerAxel Behrens USP25 promotes pathological HIF-1-driven metabolic reprogramming and is a potential therapeutic target in pancreatic cancer. Nature Communications 2022, 13, 1-18, 10.1038/s41467-022-29684-9.
  19. Claudio Scafoglio; Bruce A. Hirayama; Vladimir Kepe; Jie Liu; Chiara Ghezzi; Nagichettiar Satyamurthy; Neda A. Moatamed; Jiaoti Huang; Hermann Koepsell; Jorge R. Barrio; et al.Ernest M. Wright Functional expression of sodium-glucose transporters in cancer. Proceedings of the National Academy of Sciences 2015, 112, E4111-E4119, 10.1073/pnas.1511698112.
  20. Felipe Paredes; Holly C. Williams; Alejandra San Martin; Metabolic adaptation in hypoxia and cancer. Cancer Letters 2021, 502, 133-142, 10.1016/j.canlet.2020.12.020.
  21. Siyuan Chen; Bo Ning; Jinwen Song; Zihan Yang; Li Zhou; Zhiji Chen; Linhong Mao; Hongtao Liu; Qingliang Wang; Song He; et al.Zhihang Zhou Enhanced pentose phosphate pathway activity promotes pancreatic ductal adenocarcinoma progression via activating YAP/MMP1 axis under chronic acidosis. International Journal of Biological Sciences 2022, 18, 2304-2316, 10.7150/ijbs.69526.
  22. Su Chii Kong; Asbjørn Nøhr-Nielsen; Katrine Zeeberg; Stephan Joel Reshkin; Else Kay Hoffmann; Ivana Novak; Stine Falsig Pedersen; Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells. Pancreas 2016, 45, 1036-1047, 10.1097/mpa.0000000000000571.
  23. GuemHee Baek; Yan F. Tse; Zeping Hu; Derek Cox; Noah Buboltz; Peter McCue; Charles J. Yeo; Michael A. White; Ralph J. DeBerardinis; Erik S. Knudsen; et al.Agnieszka K. Witkiewicz MCT4 Defines a Glycolytic Subtype of Pancreatic Cancer with Poor Prognosis and Unique Metabolic Dependencies. Cell Reports 2014, 9, 2233-2249, 10.1016/j.celrep.2014.11.025.
  24. William J. Quinn; Jing Jiao; Tara TeSlaa; Jason Stadanlick; Zhonglin Wang; Liqing Wang; Tatiana Akimova; Alessia Angelin; Patrick M. Schäfer; Michelle D. Cully; et al.Caroline PerryPiotr K. KopinskiLili GuoIan A. BlairLouis R. GhanemMichael S. LeibowitzWayne W. HancockEdmund K. MoonMatthew H. LevineEvgeniy B. EruslanovDouglas C. WallaceJoseph A. BaurUlf H. Beier Lactate Limits T Cell Proliferation via the NAD(H) Redox State. Cell Reports 2020, 33, 108500-108500, 10.1016/j.celrep.2020.108500.
  25. Maria V. Liberti; Jason W. Locasale; The Warburg Effect: How Does it Benefit Cancer Cells?. Trends in Biochemical Sciences 2016, 41, 211-218, 10.1016/j.tibs.2015.12.001.
  26. Surendra K. Shukla; Vinee Purohit; Kamiya Mehla; Venugopal Gunda; Nina V. Chaika; Enza Vernucci; Ryan J. King; Jaime Abrego; Gennifer D. Goode; Aneesha Dasgupta; et al.Alysha L. IlliesTeklab GebregiworgisBingbing DaiJithesh J. AugustineDivya MurthyKuldeep S. AttriOksana MashadovaPaul M. GrandgenettRobert PowersQuan P. LyAudrey J. LazenbyJean L. GremFang YuJosé M. MatésJohn M. AsaraJung-Whan KimJordan H. HankinsColin WeekesMichael A. HollingsworthNatalie J. SerkovaAaron R. SassonJason B. FlemingJennifer M. OlivetoCostas A. LyssiotisLewis C. CantleyLyudmyla BerimPankaj K. Singh MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell 2017, 32, 392, 10.1016/j.ccell.2017.08.008.
  27. Sabine Riethdorf; Natalie Reimers; Volker Assmann; Jan-Wilhelm Kornfeld; Luigi Terracciano; Guido Sauter; Klaus Pantel; High incidence of EMMPRIN expression in human tumors. International Journal of Cancer 2006, 119, 1800-1810, 10.1002/ijc.22062.
  28. P. Kirk; M.C. Wilson; C. Heddle; M.H. Brown; A.N. Barclay; A.P. Halestrap; CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. The EMBO Journal 2000, 19, 3896-3904, 10.1093/emboj/19.15.3896.
  29. W Schneiderhan; M Scheler; K-H Holzmann; M Marx; J E Gschwend; M Bucholz; Thomas Gress; T Seufferlein; G Adler; F Oswald; et al. CD147 silencing inhibits lactate transport and reduces malignant potential of pancreatic cancer cells in in vivo and in vitro models. Gut 2009, 58, 1391-1398, 10.1136/gut.2009.181412.
  30. Krushna C. Patra; Nissim Hay; The pentose phosphate pathway and cancer. Trends in Biochemical Sciences 2014, 39, 347-354, 10.1016/j.tibs.2014.06.005.
  31. Matthew E. Bechard; Anna Word; Amanda V. Tran; Xiaojing Liu; Jason W. Locasale; Oliver G. McDonald; Pentose conversions support the tumorigenesis of pancreatic cancer distant metastases. Oncogene 2018, 37, 5248-5256, 10.1038/s41388-018-0346-5.
  32. Nicholas J Kruger; Antje von Schaewen; The oxidative pentose phosphate pathway: structure and organisation. Current Opinion in Plant Biology 2003, 6, 236-246, 10.1016/s1369-5266(03)00039-6.
  33. Anna Stincone; Alessandro Prigione; Thorsten Cramer; Mirjam M. C. Wamelink; Kate Campbell; Eric Cheung; Viridiana Olin‐Sandoval; Nana-Maria Greuning; Antje Krueger; Mohammad Tauqeer Alam; et al.Markus Andreas KellerMichael BreitenbachKevin Michael BrindleJoshua D. RabinowitzMarkus Ralser The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biological Reviews 2014, 90, 927-963, 10.1111/brv.12140.
  34. Naiara Santana Codina; Anjali A. Roeth; Yi Zhang; Annan Yang; Oksana Mashadova; John M. Asara; Xiaoxu Wang; Roderick T. Bronson; Costas A. Lyssiotis; Haoqiang Ying; et al.Alec C. Kimmelman Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis. Nature Communications 2018, 9, 1-13, 10.1038/s41467-018-07472-8.
  35. Ying Yang; Mari B. Ishak Gabra; Eric A. Hanse; Xazmin H. Lowman; Thai Q. Tran; Haiqing Li; Neta Milman; Juan Liu; Michael Reid; Jason W. Locasale; et al.Ziv GilMei Kong MiR-135 suppresses glycolysis and promotes pancreatic cancer cell adaptation to metabolic stress by targeting phosphofructokinase-1. Nature Communications 2019, 10, 1-15, 10.1038/s41467-019-08759-0.
  36. De-Hai Wu; Hao Liang; Shou-Nan Lu; Hao Wang; Zhi-Lei Su; Lei Zhang; Jian-Qun Ma; Mian Guo; Sheng Tai; Shan Yu; et al. miR-124 Suppresses Pancreatic Ductal Adenocarcinoma Growth by Regulating Monocarboxylate Transporter 1-Mediated Cancer Lactate Metabolism. Cellular Physiology and Biochemistry 2018, 50, 924-935, 10.1159/000494477.
  37. Makoto Abue; Misa Yokoyama; Rie Shibuya; Keiichi Tamai; Kazunori Yamaguchi; Ikuro Sato; Nobuyuki Tanaka; Shin Hamada; Tooru Shimosegawa; Kazuo Sugamura; et al.Kennichi Satoh Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. International Journal of Oncology 2014, 46, 539-547, 10.3892/ijo.2014.2743.
  38. Afra Z. Daoud; Eoghan Mulholland; Grace Cole; Helen O. McCarthy; MicroRNAs in Pancreatic Cancer: biomarkers, prognostic, and therapeutic modulators. BMC Cancer 2019, 19, 1-13, 10.1186/s12885-019-6284-y.
  39. Ruiyuan Xu; Jinshou Yang; Bo Ren; Huanyu Wang; Gang Yang; Yuan Chen; Lei You; Yupei Zhao; Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies. Frontiers in Oncology 2020, 10, 572722, 10.3389/fonc.2020.572722.
  40. Vinicius Cruzat; Marcelo Macedo Rogero; Kevin Noel Keane; Rui Curi; Philip Newsholme; Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients 2018, 10, 1564, 10.3390/nu10111564.
  41. Brian J. Altman; Zachary E. Stine; Chi V. Dang; From Krebs to clinic: glutamine metabolism to cancer therapy. Nature Cancer 2016, 16, 619-634, 10.1038/nrc.2016.71.
  42. Ahmad A. Cluntun; Michael J. Lukey; Richard A. Cerione; Jason W. Locasale; Glutamine Metabolism in Cancer: Understanding the Heterogeneity. Trends in Cancer 2017, 3, 169-180, 10.1016/j.trecan.2017.01.005.
  43. Jurre J. Kamphorst; Michel Nofal; Cosimo Commisso; Sean R. Hackett; Wenyun Lu; Elda Grabocka; Matthew G. Vander Heiden; George Miller; Jeffrey A. Drebin; Dafna Bar-Sagi; et al.Craig B. ThompsonJoshua D. Rabinowitz Human Pancreatic Cancer Tumors Are Nutrient Poor and Tumor Cells Actively Scavenge Extracellular Protein. Cancer Research 2015, 75, 544-553, 10.1158/0008-5472.can-14-2211.
  44. Alex J. Bott; Jianliang Shen; Claudia Tonelli; Le Zhan; Nithya Sivaram; Ya-Ping Jiang; Xufen Yu; Vrushank Bhatt; Eric Chiles; Hua Zhong; et al.Sara MaimouniWeiwei DaiStephani VelasquezJi-An PanNathiya MuthalaguJennifer MortonTracy G. AnthonyHui FengWouter H. LamersDaniel J. MurphyJessie Yanxiang GuoJian JinHoward C. CrawfordLanjing ZhangEileen WhiteRichard Z. LinXiaoyang SuDavid A. TuvesonWei-Xing Zong Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism. Cell Reports 2019, 29, 1287-1298.e6, 10.1016/j.celrep.2019.09.056.
  45. Gabriela Reyes-Castellanos; Nadine Abdel Hadi; Alice Carrier; Autophagy Contributes to Metabolic Reprogramming and Therapeutic Resistance in Pancreatic Tumors. Cells 2022, 11, 426, 10.3390/cells11030426.
  46. Chia-Jung Li; Wan-Ting Liao; Meng-Yu Wu; Pei-Yi Chu; New Insights into the Role of Autophagy in Tumor Immune Microenvironment. International Journal of Molecular Sciences 2017, 18, 1566, 10.3390/ijms18071566.
  47. Cosimo Commisso; Shawn M. Davidson; Rengin G. Soydaner-Azeloglu; Seth J. Parker; Jurre J. Kamphorst; Sean Hackett; Elda Grabocka; Michel Nofal; Jeffrey A. Drebin; Craig B. Thompson; et al.Joshua D. RabinowitzChristian M. MetalloMatthew G. Vander HeidenDafna Bar-Sagi Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 2013, 497, 633-637, 10.1038/nature12138.
  48. David R. Wise; Ralph J. DeBerardinis; Anthony Mancuso; Nabil Sayed; Xiao-Yong Zhang; Harla K. Pfeiffer; Ilana Nissim; Evgueni Daikhin; Marc Yudkoff; Steven B. McMahon; et al.Craig B. Thompson Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proceedings of the National Academy of Sciences 2008, 105, 18782-18787, 10.1073/pnas.0810199105.
  49. Dafna Bar-Sagi; James R. Feramisco; Induction of Membrane Ruffling and Fluid-Phase Pinocytosis in Quiescent Fibroblasts by ras Proteins. Science 1986, 233, 1061-1068, 10.1126/science.3090687.
  50. Natalie Porat-Shliom; Yoel Kloog; Julie G. Donaldson; A Unique Platform for H-Ras Signaling Involving Clathrin-independent Endocytosis. Molecular Biology of the Cell 2008, 19, 765-775, 10.1091/mbc.e07-08-0841.
  51. Ju-Won Seo; Jungwon Choi; So-Yeon Lee; Suhyun Sung; Hyun Ju Yoo; Min-Ji Kang; Heesun Cheong; Jaekyoung Son; Autophagy is required for PDAC glutamine metabolism. Scientific Reports 2016, 6, 37594, 10.1038/srep37594.
  52. Bryce W. Carey; Lydia W. S. Finley; Justin R. Cross; C. David Allis; Craig B. Thompson; Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 2014, 518, 413-416, 10.1038/nature13981.
  53. Thai Q. Tran; Mari B. Ishak Gabra; Xazmin H. Lowman; Ying Yang; Michael Reid; Min Pan; Timothy R. O’Connor; Mei Kong; Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes. PLOS Biology 2017, 15, e2002810-e2002810, 10.1371/journal.pbio.2002810.
  54. Seth J. Parker; Caroline R. Amendola; Kate E. R. Hollinshead; Qijia Yu; Keisuke Yamamoto; Joel Encarnación-Rosado; Rebecca E. Rose; Madeleine M. LaRue; Albert S. W. Sohn; Doug E. Biancur; et al.Joao A. PauloSteven P. GygiDrew R. JonesHuamin WangMark R. PhilipsDafna Bar-SagiJoseph D. ManciasAlec C. Kimmelman Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer. Cancer Discovery 2020, 10, 1018-1037, 10.1158/2159-8290.cd-19-0959.
  55. Nadine Sperb; Miltiadis Tsesmelis; Thomas Wirth; Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma. International Journal of Molecular Sciences 2020, 21, 5486, 10.3390/ijms21155486.
  56. Jakob Michael Riedl; Florian Posch; Gerald Prager; Wolfgang Eisterer; Leopold Oehler; Thamer Sliwa; Klaus Wilthoner; Andreas Petzer; Petra Pichler; Eva Hubmann; et al.Thomas WinderSonja BurgstallerMarkus KorgerJohannes AndelRichard GreilHans-Joerg NeumannMartin PecherstorferKathrin Philipp-AbbrederisAngela DjananiBirgit GruenbergerFriedrich LaengleEwald WöllArmin Gerger The AST/ALT (De Ritis) ratio predicts clinical outcome in patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine: post hoc analysis of an Austrian multicenter, noninterventional study. Therapeutic Advances in Medical Oncology 2020, 12, 1243, 10.1177/1758835919900872.
  57. Orianne Olivares; Jared R. Mayers; Victoire Gouirand; Margaret E. Torrence; Tristan Gicquel; Laurence Borge; Sophie Lac; Julie Roques; Marie-Noëlle Lavaut; Patrice Berthezène; et al.Marion RubisVeronique SecqStéphane GarciaVincent MoutardierDominique LombardoJuan Lucio IovannaRichard TomasiniFabienne GuillaumondMatthew G. Vander HeidenSophie Vasseur Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nature Communications 2017, 8, 16031-16031, 10.1038/ncomms16031.
  58. Mylène Tajan; Andreas K. Hock; Julianna Blagih; Neil A. Robertson; Christiaan F. Labuschagne; Flore Kruiswijk; Timothy J. Humpton; Peter D. Adams; Karen H. Vousden; A Role for p53 in the Adaptation to Glutamine Starvation through the Expression of SLC1A3. Cell Metabolism 2018, 28, 721-736.e6, 10.1016/j.cmet.2018.07.005.
  59. Ru Chen; Lisa A Lai; Yumi Sullivan; Melissa Wong; Lei Wang; Jonah Riddell; Linda Jung; Venu G. Pillarisetty; Teresa A. Brentnall; Sheng Pan; et al. Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer. Scientific Reports 2017, 7, 1-14, 10.1038/s41598-017-08436-6.
  60. Claudia C.S. Chini; Anatilde M. Gonzalez Guerrico; Veronica Nin; Juliana Camacho-Pereira; Carlos Escande; Maria Thereza Barbosa; Eduardo N. Chini; Targeting of NAD Metabolism in Pancreatic Cancer Cells: Potential Novel Therapy for Pancreatic Tumors. Clinical Cancer Research 2014, 20, 120-130, 10.1158/1078-0432.ccr-13-0150.
  61. Oliver Maddocks; Dimitris Athineos; Eric C. Cheung; Pearl Lee; Tong Zhang; Niels J. F. Van Den Broek; Gillian M. Mackay; Christiaan F. Labuschagne; David Michael Gay; Flore Kruiswijk; et al.Julianna BlagihDavid F. VincentKirsteen J. CampbellFatih CeteciOwen J. SansomKaren BlythKaren H. Vousden Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 2017, 544, 372-376, 10.1038/nature22056.
  62. Michael A. Badgley; Daniel M. Kremer; H. Carlo Maurer; Kathleen E. DelGiorno; Ho-Joon Lee; Vinee Purohit; Irina R. Sagalovskiy; Alice Ma; Jonathan Kapilian; Christina E. M. Firl; et al.Amanda R. DeckerSteve A. SastraCarmine F. PalermoLeonardo R. AndradePeter SajjakulnukitLi ZhangZachary P. TolstykaTal HirschhornCandice LambTong LiuWei GuE. Scott SeeleyEverett StoneGeorge GeorgiouUri ManorAlina IugaGeoffrey M. WahlBrent R. StockwellCostas A. LyssiotisKenneth P. Olive Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020, 368, 85-89, 10.1126/science.aaw9872.
  63. Marco E. Bianchi; DAMPs, PAMPs and alarmins: all we need to know about danger. Journal of Leukocyte Biology 2006, 81, 1-5, 10.1189/jlb.0306164.
  64. J. M. Genkinger; C. M. Kitahara; L. Bernstein; A. Berrington de Gonzalez; M. Brotzman; J. W. Elena; G. G. Giles; P. Hartge; P. N. Singh; R. Z. Stolzenberg-Solomon; et al.E. WeiderpassH.-O. AdamiK. E. AndersonL. E. Beane-FreemanJ. E. BuringG. E. FraserC. S. FuchsS. M. GapsturJ. M. GazianoK. J. HelzlsouerJ. V. LaceyM. S. LinetJ. J. LiuY. ParkU. PetersM. P. PurdueK. RobienC. SchairerH. D. SessoK. VisvanathanE. WhiteA. WolkB. M. WolpinA. Zeleniuch-JacquotteE. J. Jacobs Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies. Annals of Oncology 2015, 26, 2257-2266, 10.1093/annonc/mdv355.
  65. Tobiloba E. Oni; Giulia Biffi; Lindsey A. Baker; Yuan Hao; Claudia Tonelli; Tim D.D. Somerville; Astrid Deschênes; Pascal Belleau; Chang-Il Hwang; Francisco J. Sánchez-Rivera; et al.Hilary CoxErin BrosnanAbhishek DoshiRebecca P. LumiaKimia KhalediYoungkyu ParkLloyd C. TrotmanScott W. LoweAlexander KrasnitzChristopher R. VakocDavid A. Tuveson SOAT1 promotes mevalonate pathway dependency in pancreatic cancer. Journal of Experimental Medicine 2020, 217, 321, 10.1084/jem.20192389.
  66. Linara Gabitova-Cornell; Aizhan Surumbayeva; Suraj Peri; Janusz Franco-Barraza; Diana Restifo; Nicole Weitz; Charline Ogier; Aaron R. Goldman; Tiffiney R. Hartman; Ralph Francescone; et al.Yinfei TanEmmanuelle NicolasNeelima ShahElizabeth A. HandorfKathy Q. CaiAlana M. O'ReillyIdo SlomaRachel ChiaverelliRichard A. MoffittVladimir KhazakCarolyn Y. FangErica A. GolemisEdna CukiermanIgor Astsaturov Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer. Cancer Cell 2020, 38, 567-583.e11, 10.1016/j.ccell.2020.08.015.
  67. Sandrine Silvente-Poirot; Marc Poirot; Cholesterol and Cancer, in the Balance. Science 2014, 343, 1445-1446, 10.1126/science.1252787.
  68. P Clerc; N Bensaadi; P Pradel; A Estival; F Clemente; N Vaysse; Lipid-dependent proliferation of pancreatic cancer cell lines.. Cancer Research 1991, 51, 435.
  69. Julian Swierczynski; Areta Hebanowska; Tomasz Sledzinski; Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. World Journal of Gastroenterology 2014, 20, 725, 10.3748/wjg.v20.i9.2279.
  70. Kim Walter; Seung-Mo Hong; Sinead Nyhan; Marcia Canto; Neal Fedarko; Alison Klein; Margaret Griffith; Noriyuki Omura; Susan Medghalchi; Frank Kuhajda; et al.Michael Goggins Serum Fatty Acid Synthase as a Marker of Pancreatic Neoplasia. Cancer Epidemiology, Biomarkers & Prevention 2009, 18, 2380-2385, 10.1158/1055-9965.epi-09-0144.
  71. Yan Sun; Weiwei He; Man Luo; Yuhong Zhou; Guilin Chang; Weiying Ren; Kefen Wu; Chang Guilin; Jiping Shen; Xiaoping Zhao; et al.Yu Hu SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism. Tumor Biology 2015, 36, 4133-4141, 10.1007/s13277-015-3047-5.
  72. Saber Tadros; Surendra K. Shukla; Ryan J. King; Venugopal Gunda; Enza Vernucci; Jaime Abrego; Nina V. Chaika; Fang Yu; Audrey J. Lazenby; Lyudmyla Berim; et al.Jean GremAaron R. SassonPankaj K. Singh De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer. Cancer Research 2017, 77, 5503-5517, 10.1158/0008-5472.can-16-3062.
  73. Youyun Yang; Hailan Li; Zhaomin Li; Zijin Zhao; Michelle Yip-Schneider; Qipeng Fan; C. Max Schmidt; E. Gabriela Chiorean; Jingwu Xie; Liang Cheng; et al.Jey-Hsin ChenJian-Ting Zhang Role of fatty acid synthase in gemcitabine and radiation resistance of pancreatic cancers. International journal of biochemistry and molecular biology 2011, 2, 89-98.
  74. Cody N. Rozeveld; Katherine M. Johnson; Lizhi Zhang; Gina L. Razidlo; KRAS Controls Pancreatic Cancer Cell Lipid Metabolism and Invasive Potential through the Lipase HSL. Cancer Research 2020, 80, 4932-4945, 10.1158/0008-5472.can-20-1255.
  75. Knut Tomas Dalen; Stine M. Ulven; Borghild M. Arntsen; Karianne Solaas; Hilde I. Nebb; PPARα activators and fasting induce the expression of adipose differentiation-related protein in liver. Journal of Lipid Research 2006, 47, 931-943, 10.1194/jlr.m500459-jlr200.
  76. Benny Hung-Junn Chang; Lan Li; Antoni Paul; Susumu Taniguchi; Vijayalakshmi Nannegari; William C. Heird; Lawrence Chan; Protection against Fatty Liver but Normal Adipogenesis in Mice Lacking Adipose Differentiation-Related Protein. Molecular and Cellular Biology 2006, 26, 1063-1076, 10.1128/mcb.26.3.1063-1076.2006.
  77. Yuki Hashimoto; Mitsuaki Ishida; Hironori Ryota; Tomohisa Yamamoto; Hisashi Kosaka; Satoshi Hirooka; So Yamaki; Masaya Kotsuka; Yoichi Matsui; Hiroaki Yanagimoto; et al.Koji TsutaSohei Satoi Adipophilin expression is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma: An immunohistochemical analysis. Pancreatology 2019, 19, 443-448, 10.1016/j.pan.2019.03.001.
  78. Elaine Chen; Tsung Huang Tsai; Lan Li; Pradip Saha; Lawrence Chan; Benny Hung-Junn Chang; PLIN2 is a Key Regulator of the Unfolded Protein Response and Endoplasmic Reticulum Stress Resolution in Pancreatic β Cells. Scientific Reports 2017, 7, 40855, 10.1038/srep40855.
  79. Susanne M. Schmidt; Kerstin Schag; Martin R. Müller; Toni Weinschenk; Silke Appel; Oliver Schoor; Markus M. Weck; Frank Grünebach; Lothar Kanz; Stefan Stevanovic; et al.Hans-Georg RammenseePeter Brossart Induction of Adipophilin-Specific Cytotoxic T Lymphocytes Using a Novel HLA-A2-Binding Peptide That Mediates Tumor Cell Lysis. Cancer Research 2004, 64, 1164-1170, 10.1158/0008-5472.can-03-2538.
  80. Adrian M. Seifert; Charlotte Reiche; Max Heiduk; Anna Tannert; Ann-Christin Meinecke; Stephanie Baier; Janusz von Renesse; Christoph Kahlert; Marius Distler; Thilo Welsch; et al.Christoph ReissfelderDaniela E. AustGeorge MillerJürgen WeitzLena Seifert Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels. Oncogene 2020, 39, 3102-3113, 10.1038/s41388-020-1186-7.
  81. Yijia He; Yuexin Dong; Xinwen Zhang; Zhuang Ding; Yuxian Song; Xiaofeng Huang; Sheng Chen; Zhiyong Wang; Yanhong Ni; Liang Ding; et al. Lipid Droplet-Related PLIN2 in CD68+ Tumor-Associated Macrophage of Oral Squamous Cell Carcinoma: Implications for Cancer Prognosis and Immunotherapy. Frontiers in Oncology 2022, 12, 287, 10.3389/fonc.2022.824235.
  82. Bincy Philip; Christina L. Roland; Jaroslaw Daniluk; Yan Liu; Deyali Chatterjee; Sobeyda B. Gomez; Baoan Ji; Haojie Huang; Huamin Wang; Jason B. Fleming; et al.Craig D. LogsdonZobeida Cruz-Monserrate A High-Fat Diet Activates Oncogenic Kras and COX2 to Induce Development of Pancreatic Ductal Adenocarcinoma in Mice. Gastroenterology 2013, 145, 1449-1458, 10.1053/j.gastro.2013.08.018.
  83. Katherine Minjee Chung; Jaffarguriqbal Singh; Lauren Lawres; Kimberly Judith Dorans; Cathy Garcia; Daniel Burkhardt; Rebecca Robbins; Arjun Bhutkar; Rebecca Cardone; Xiaojian Zhao; et al.Ana BabicSara VäyrynenAndressa Dias CostaJonathan A. NowakDaniel T. ChangRichard F. DunneAram F. HezelAlbert C. KoongJoshua J. WilhelmMelena D. BellinVibe NylanderAnna L. GloynMark I. McCarthyRichard G. KibbeySmita KrishnaswamyBrian M. WolpinTyler JacksCharles S. FuchsMandar Deepak Muzumdar Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma. Cell 2020, 181, 832-847.e18, 10.1016/j.cell.2020.03.062.
  84. Andrew S. Greenberg; Rosalind A. Coleman; Fredric B. Kraemer; James L. McManaman; Martin S. Obin; Vishwajeet Puri; Qing-Wu Yan; Hideaki Miyoshi; Douglas G. Mashek; The role of lipid droplets in metabolic disease in rodents and humans. Journal of Clinical Investigation 2011, 121, 2102-2110, 10.1172/jci46069.
  85. James A. Olzmann; Pedro Carvalho; Dynamics and functions of lipid droplets. Nature Reviews Molecular Cell Biology 2018, 20, 137-155, 10.1038/s41580-018-0085-z.
  86. Fabienne Guillaumond; Ghislain Bidaut; Mehdi Ouaissi; Stéphane Servais; Victoire Gouirand; Orianne Olivares; Sophie Lac; Laurence Borge; Julie Roques; Odile Gayet; et al.Michelle PinaultCyrille GuimaraesJérémy NigriCéline LoncleMarie-Noëlle LavautStéphane GarciaAnne TailleuxBart StaelsEzequiel CalvoRichard TomasiniJuan Lucio IovannaSophie Vasseur Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. Proceedings of the National Academy of Sciences 2015, 112, 2473-2478, 10.1073/pnas.1421601112.
  87. Jurre J. Kamphorst; Justin R. Cross; Jing Fan; Elisa de Stanchina; Robin Mathew; Eileen P. White; Craig B. Thompson; Joshua D. Rabinowitz; Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proceedings of the National Academy of Sciences 2013, 110, 8882-8887, 10.1073/pnas.1307237110.
  88. Mahesh S. Padanad; Georgia Konstantinidou; Niranjan Venkateswaran; Margherita Melegari; Smita Rindhe; Matthew Mitsche; Chendong Yang; Kimberly Batten; Kenneth E. Huffman; Jingwen Liu; et al.Ximing TangJaime Rodriguez-CanalesNeda KalhorJerry W. ShayJohn D. MinnaJeffrey McDonaldIgnacio I. WistubaRalph J. DeBerardinisPier Paolo Scaglioni Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. Cell Reports 2016, 16, 1614-1628, 10.1016/j.celrep.2016.07.009.
  89. Frits Kamp; James Hamilton; How fatty acids of different chain length enter and leave cells by free diffusion. Prostaglandins, Leukotrienes and Essential Fatty Acids 2006, 75, 149-159, 10.1016/j.plefa.2006.05.003.
  90. Matteo Rossi Sebastiano; Georgia Konstantinidou; Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy. International Journal of Molecular Sciences 2019, 20, 3624, 10.3390/ijms20153624.
  91. Maria Saliakoura; Matteo Rossi Sebastiano; Ioanna Nikdima; Chiara Pozzato; Georgia Konstantinidou; Restriction of extracellular lipids renders pancreatic cancer dependent on autophagy. Journal of Experimental & Clinical Cancer Research 2022, 41, 1-13, 10.1186/s13046-021-02231-y.
  92. Jessica Brandi; Ilaria Dando; Elisa Dalla Pozza; Giulia Biondani; Rosalind Jenkins; Victoria Elliott; Kevin Park; Giuseppina Fanelli; Lello Zolla; Eithne Costello; et al.Aldo ScarpaDaniela CecconiMarta Palmieri Proteomic analysis of pancreatic cancer stem cells: Functional role of fatty acid synthesis and mevalonate pathways. Journal of Proteomics 2017, 150, 310-322, 10.1016/j.jprot.2016.10.002.
  93. Claudia Di Carlo; Bebiana C. Sousa; Marcello Manfredi; Jessica Brandi; Elisa Dalla Pozza; Emilio Marengo; Marta Palmieri; Ilaria Dando; Michael J. O. Wakelam; Andrea F. Lopez-Clavijo; et al.Daniela Cecconi Integrated lipidomics and proteomics reveal cardiolipin alterations, upregulation of HADHA and long chain fatty acids in pancreatic cancer stem cells. Scientific Reports 2021, 11, 1-13, 10.1038/s41598-021-92752-5.
  94. Mohammed El-Hafidi; Francisco Correa; Cecilia Zazueta; Mitochondrial dysfunction in metabolic and cardiovascular diseases associated with cardiolipin remodeling. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2020, 1866, 165744, 10.1016/j.bbadis.2020.165744.
  95. Kathy Pfeiffer; Vishal Gohil; Rosemary A. Stuart; Carola Hunte; Ulrich Brandt; Miriam L. Greenberg; Hermann Schägger; Cardiolipin Stabilizes Respiratory Chain Supercomplexes. Journal of Biological Chemistry 2003, 278, 52873-52880, 10.1074/jbc.m308366200.
  96. Denise Wolrab; Robert Jirásko; Eva Cífková; Marcus Höring; Ding Mei; Michaela Chocholoušková; Ondřej Peterka; Jakub Idkowiak; Tereza Hrnčiarová; Ladislav Kuchař; et al.Robert AhrendsRadana BrumarováDavid FriedeckýGabriel Vivo-TruyolsPavel ŠkrhaJan ŠkrhaRadek KučeraBohuslav MelicharGerhard LiebischRalph BurkhardtMarkus R. WenkAmaury Cazenave-GassiotPetr KarásekIvo NovotnýKristína GreplováRoman HrstkaMichal Holčapek Lipidomic profiling of human serum enables detection of pancreatic cancer. Nature Communications 2022, 13, 1-16, 10.1038/s41467-021-27765-9.
  97. Julia Mayerle; Holger Kalthoff; Regina Reszka; Beate Kamlage; Erik Peter; Bodo Schniewind; Sandra González Maldonado; Christian Pilarsky; Claus-Dieter Heidecke; Philipp Schatz; et al.Marius DistlerJonas A ScheiberUjjwal M MahajanF Ulrich WeissRobert GrützmannMarkus M Lerch Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. Gut 2017, 67, 128-137, 10.1136/gutjnl-2016-312432.
  98. Johannes F Fahrmann; Leonidas E Bantis; Michela Capello; Ghislaine Scelo; Jennifer B Dennison; Nikul Patel; Eunice Murage; Jody Vykoukal; Deepali L Kundnani; Lenka Foretova; et al.Eleonora FabianovaIvana HolcatovaVladimir JanoutZiding FengMichele Yip-SchneiderJianjun ZhangRandall BrandAyumu TaguchiAnirban MaitraPaul BrennanC Max SchmidtSamir Hanash A Plasma-Derived Protein-Metabolite Multiplexed Panel for Early-Stage Pancreatic Cancer. JNCI: Journal of the National Cancer Institute 2018, 111, 372-379, 10.1093/jnci/djy126.
  99. Guangxi Wang; Hantao Yao; Yan Gong; Zipeng Lu; Ruifang Pang; Yang Li; Yuyao Yuan; Huajie Song; Jia Liu; Yan Jin; et al.Yongsu MaYinmo YangHonggang NieGuangze ZhangZhu MengZhe ZhouXuyang ZhaoMantang QiuZhicheng ZhaoKuirong JiangQiang ZengLimei GuoYuxin Yin Metabolic detection and systems analyses of pancreatic ductal adenocarcinoma through machine learning, lipidomics, and multi-omics. Science Advances 2021, 7, 456, 10.1126/sciadv.abh2724.
  100. Rocio I. R. Macias; Luis Muñoz-Bellvís; Anabel Sánchez-Martín; Enara Arretxe; Ibon Martínez-Arranz; Ainhoa Lapitz; M. Laura Gutiérrez; Adelaida La La Casta; Cristina Alonso; Luis M. González; et al.Matias A. AvilaMaria L. Martinez-ChantarRui E. CastroLuis BujandaJesus M. BanalesJose J. G. Marin A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma. Cancers 2020, 12, 1433, 10.3390/cancers12061433.
  101. Sebastian Doll; Bettina Proneth; Yulia Tyurina; Elena Panzilius; Sho Kobayashi; Irina Ingold; Martin Irmler; Martin Irmler Johannes Beckers; Michaela Aichler; Michaela Aichler Axel Walch; et al.Holger ProkischDietrich TrümbachGaowei MaoFeng QuHulya BayirJoachim FüllekrugElena Panzilius Christina H ScheelWolfgang WurstJoel SchickValerian E. KaganJosé Pedro Friedmann AngeliMarcus Conrad ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nature Chemical Biology 2016, 13, 91-98, 10.1038/nchembio.2239.
  102. Nanjun Hu; Lulu Bai; Enyong Dai; Leng Han; Rui Kang; Hongjun Li; Daolin Tang; Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis. Biochemical and Biophysical Research Communications 2020, 536, 100-106, 10.1016/j.bbrc.2020.12.066.
More
Information
Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : , , , , , , , , ,
View Times: 443
Revisions: 6 times (View History)
Update Date: 30 Aug 2022
1000/1000
Video Production Service