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
Cenap Güngör
 -- 3506 2022-08-26 09:47:07 |
2 Adjust the ref format
Lindsay Dong
-13 word(s) 3493 2022-08-29 07:03:21 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Wang, D.;  Li, Y.;  Ge, H.;  Ghadban, T.;  Reeh, M.;  Güngör, C. The Extracellular Matrix in Pancreatic Ductal Adenocarcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/26531 (accessed on 01 July 2024).
Wang D,  Li Y,  Ge H,  Ghadban T,  Reeh M,  Güngör C. The Extracellular Matrix in Pancreatic Ductal Adenocarcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/26531. Accessed July 01, 2024.
Wang, Dan, Yuqiang Li, Heming Ge, Tarik Ghadban, Matthias Reeh, Cenap Güngör. "The Extracellular Matrix in Pancreatic Ductal Adenocarcinoma" Encyclopedia, https://encyclopedia.pub/entry/26531 (accessed July 01, 2024).
Wang, D.,  Li, Y.,  Ge, H.,  Ghadban, T.,  Reeh, M., & Güngör, C. (2022, August 26). The Extracellular Matrix in Pancreatic Ductal Adenocarcinoma. In Encyclopedia. https://encyclopedia.pub/entry/26531
Wang, Dan, et al. "The Extracellular Matrix in Pancreatic Ductal Adenocarcinoma." Encyclopedia. Web. 26 August, 2022.
The Extracellular Matrix in Pancreatic Ductal Adenocarcinoma
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers14163998

Pancreatic ductal adenocarcinoma (PDAC) is rich in dense fibrotic stroma that are composed of extracellular matrix (ECM) proteins. A disruption of the balance between ECM synthesis and secretion and the altered expression of matrix remodeling enzymes lead to abnormal ECM dynamics in PDAC. This pathological ECM promotes cancer growth, survival, invasion, and alters the behavior of fibroblasts and immune cells leading to metastasis formation and chemotherapy resistance, which contribute to the high lethality of PDAC. Additionally, recent evidence highlights that ECM, as a major structural component of the tumor microenvironment, is a highly dynamic structure in which ECM proteins establish a physical and biochemical niche for cancer stem cells (CSCs). CSCs are characterized by self-renewal, tumor initiation, and resistance to chemotherapeutics. 

pancreatic ductal adenocarcinoma extracellular matrix cancer stem cells chemotherapy resistance metastasis

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers in the world, with a dismal overall 5-year survival rate of about 9% [1]. Some studies predict PDAC will be on track to develop into the second leading cause of cancer death by 2030 [2][3]. Unfortunately, a large proportion of patients have locally advanced stages or regional/distant metastatic spread at the time of initial diagnosis, making the majority of patients not suitable for curative surgery [4]. Although great progress has been made in the treatment of PDAC, such as chemotherapy, radiotherapy, and molecular targeting, it is still challenging that many patients show intrinsically or acquired resistance to these treatments, and the therapeutic effect and benefit is often limited [5][6]. Although neglected for many years, much attention has been paid to investigate the local tumor microenvironment. It has been found that the abnormal dynamics of the extracellular matrix (ECM) is a major promoting factor for early metastasis and drug resistance of PDAC cells [7][8].
The ECM consists of numerous structural proteins such as collagen, proteoglycan and glycoproteins, and stromal cell proteins (non-structural proteins) [9]. In principle, the ECM is not a static network scaffold, but regulates its biochemical function and biomechanical properties by dynamically regulating its composition, post-translational modifications, and structure [10]. Physiologically, mammalian cells and ECM are closely intermediated through various soluble factors such as cytokines, chemokines, costimulatory molecules, additional biological mediators (oxidants and prostaglandins), and physical stimuli such as microenvironmental stiffness and tension/compression forces [11]. The ECM represents a dynamic ecological niche in tumor development, with specific physical, biochemical, and biomechanical properties that help to maintain the homeostasis of cells, tissues, and organs [12]. Metastasis formation of invasive tumors is a complex and discrete series of various biological steps, but each step seems to be related to the dynamic regulation of ECM components and its post-translational modifications [13]. Changes in the ECM can directly induce cell transformation and metastasis to promote tumor initiation and progression [14]. A well-known clinical characteristic of PDAC is a strong desmoplastic reaction that is induced by cancer cells. This desmoplasia, defined as the growth of fibrous or connective tissue, is strongly associated with malignant neoplasms and causes a dense fibrosis around the tumor, tissue hypervascularization, and suppression of immune cells. This dense fibrotic matrix is interwoven with the ECM and is thought to provide a physical barrier protection for tumor cells. In addition, the deposition of large amounts of ECM proteins is common in solid tumors such as PDAC and is known as a pro-connective tissue hyperplasia response, which regulates stromal cell behavior, determines tumor-related inflammation and angiogenesis, and promotes a pro-tumor microenvironment [15].
In summary, the cross-regulation and interaction network of ECM is crucial for metastasis and chemotherapy resistance of PDAC. The dynamic environment of ECM provides a reservoir for various oncogenic signaling molecules and supports the regulation of CSCs through mechanical forces and biochemical signals, thus promoting tumor cell metastasis and chemotherapy resistance.

2. ECM in PDAC

Abnormal remodeling of the ECM is associated with a variety of pathologic conditions, such as inflammation, fibrosis, and cancer [16]. In particular, a growing number of studies have highlighted the active role of dysregulated ECM dynamics in tumor progression and invasion [17][18]. The expression of many ECM remodeling enzymes is frequently deregulated in human cancers, most notably Matrix metalloproteinases (MMPs) [19]. MMPs are secreted by cancer-associated fibroblasts (CAFs) in PDAC [20]. Fibroblasts in the tumor microenvironment, collectively referred to as CAFs, are associated with tumor aggressiveness and reduced survival [21][22]. The CAF population, due to the different cellular origins, exhibits marked heterogeneity and functional diversity [23]. One of the most common cellular origins of CAFs is pancreatic stellate cells (PSCs) [24]. After pancreatic injury, or TGF-β stimulation, PSCs were activated, resulting in changes in cell morphology from stellate to spindle, increased nuclear volume, and decreased vitamin A droplets [25][26][27]. CAFs can also originate from tissue-resident fibroblasts, which can be activated under the control of growth factors (such as TGF-β) [28]. Additional studies have demonstrated that CAFs may also arise from trans-differentiation of non-fibroblast lineages or epithelial cells, as well as the recruitment and differentiation of bone marrow-derived mesenchymal stem cells [20][29]. Markers that were used to distinguish different CAF subsets include α-SMA, platelet-derived growth factor receptors α and β (PDGFRα/β), FAP, and Ca2+ binding protein (S100A4), but none of them are exclusively expressed by CAFs [29][30]. In terms of functional diversity, CAFs can secrete MMP, which promotes the degradation of the ECM and the release of various factors, and leads to the recruitment of some specific cells and various cytokines. On the other hand, CAFs are mainly responsible for the deposition of dense tumor stroma, which can serve as a structural scaffold for cell interactions and a physical barrier against immune infiltration. Furthermore, many growth factors and proinflammatory cytokines, including interleukin 6 (IL-6), TGF-β, and vascular endothelial growth factor (VEGF) can be produced by CAFs, which can promote tumor growth, angiogenesis, and assists in immune escape [20][31]. Therefore, CAFs, combining the above characteristics, are often programmed into three different subgroups: “antigen-presenting”, “myofibroblastic”, and “inflammatory” CAFs [32].
The dysregulation of ECM remodeling can cause mutant cells to escape apoptosis due to the pro- and anti-apoptotic effects of various ECM components or their functional fragments [33]. Abnormal ECM remodeling affects the behavior of not only cancer cells, but also those of stromal, endothelial, and immune cells of the local microenvironment as well [34][35]. Angiogenesis that is induced by abnormal ECM remodeling often results in an abnormal vasculature that is characterized by tortuous and immature leaky vessels in malignancies [36]. Vascular abnormalities, including the absence of a lymphatic network within the tumor, lead to increased interstitial fluid pressure, acidosis, and hypoxia, which underlie metastasis and drug resistance [37]. IL-6 that is secreted by stromal CAFs recruits tumor-associated macrophages and promotes their transition to an immunosuppressive phenotype (M2) [38]. Stromal CAFs recruit and induce Treg differentiation to suppress antitumor immunity and similarly enhance the tumor-promoting function of CD4+ helper T (Th) lymphocytes [39]. 
A prominent feature of PDAC is a strong pro-fibrotic response leading to a hyper-fibrotic stroma. Sparse vascularization and abundant deposition of extracellular components lay the groundwork for the stroma of PDAC [40]. Collagen, produced mainly by CAFs (especially derived from PSCs), is the most representative component of PDAC connective tissue [41]. Fibrinous collagen Type I and III account for more than 90% of the total and protein levels of these collagen proteins that increased nearly three-fold during the progression of PDAC [42]. However, compared with normal tissue, the ratio of these two kinds of collagen in tumor connective tissue did not change significantly, so one should pay attention to other differentially expressed collagen in the process of PDAC [43]. 
Proteoglycans and glycoproteins are composed of core proteins that undergo post-translational glycosylation, which largely shapes their conformation and cell signaling functions, and has important effects on tumor cells [44]. Most subunits of laminin, a small leucine-rich proteoglycan, are overexpressed in PDAC and are related to poor prognosis [45]. In particular, Lm332 and Lm511/521, which are currently common in various tumors, promote tumor progression by interacting with other proteins and cytokines [46]. The interaction of Lm332 with collagen Type VII and integrin α3β1 promotes tumor cell growth and metastasis, respectively [47][48]. Fibronectin has been shown to act as scaffolds and regulate cellular processes in the PDAC microenvironment [49]. Fibronectin stimulates tumor cell proliferation and invasion of the basement membrane and acts as a bridging molecule between ECM collagen and integrin [50][51]. Moreover, studies have shown that reduced galectin-1 (GAL1) in mouse models leads to reduced matrix activation and increased cytotoxic T-cell infiltration [52]. GAL1, as a class of glycoproteins, is expressed in multiple tumor types and is involved in proliferation, invasion, angiogenesis, metastasis, and is associated with patient survival [53][54]. 
Compared with normal pancreas, the total glycosaminoglycan content was significantly increased in PDAC (four-fold, p ≤ 0.001), mainly due to increased hyaluronic acid content [55]. A large amount of hyaluronic acid is already produced in the tumor microenvironment in the pre-cancerous intraepithelial neoplasia (PanIN) stage [56]. Hyaluronic acid is thought to be deposited primarily by CAFs and to some extent by PDAC cells [57][58]. Most importantly, hyaluronidase breaks down the hyaluronic acid matrix to allow interactions between growth factors and growth factor receptors, promoting glucose metabolism, tumor cell proliferation, and migration [59].
PSCs are key to maintaining the balance between ECM synthesis and degradation, and most studies showed an “activated” state in PDAC, leading to excessive deposition of ECM proteins [60]. It also leads to the increased expression of collagen, αSMA, immunomodulatory and other pro-tumorigenic genes [60]. TGF-β promotes ECM deposition and tumor progression in late stages of carcinogenesis [61]. As a potent activator of PSC, TGF-β mediates the interaction between the tumor microenvironment and tumor cells by binding to TGF-β cell surface receptors, promoting the deposition of ECM proteins including fibronectin and collagen [62]. The PSCs, once activated, further modulates ECM through various mechanisms. Previous studies have suggested that tissue stiffness can enhance the proliferation of tumor cells [63]. Collagen cross-linking by Lysyl-oxidase (LOX) and Tissue-transglutaminase 2 (TG2) enhances matrix stiffening [64][65]. Driven by TG2 and/or LOX, additional cross-linked collagen and rigid ECM activate Yes-associated protein (YAP) and the transcriptional coactivators of PDZ-binding motifs (TAZ), which enhances cell proliferation [66]. The stiffened ECM matrix in turn regulates the activity of ECM MMPs, Vimentin, and E-cadherin [66][67].

3. ECM and Pancreatic Cancer Stem Cells (PCSCs)

The tumorigenic ability of each PDAC cell is heterogenous, and the development and proliferation of PDAC are highly dependent on the restricted PDAC cell subpopulation, namely pancreatic cancer stem cells (PCSCs) [68]. The activity of stem cells is dependent on exogenous niche factors in normal tissues and organs. Similarly, significant changes within the tumor microenvironment in PDAC can have a similar effect on PCSCs. The tumor microenvironment of PDAC strongly promotes fibroplasia, in which the ECM interacts with integrins (including integrin subunits β1, α6, and β3) to regulate PCSCs function by influencing autocrine and paracrine signaling pathways [69]. Type 1 collagen is the main scaffold for CD133-positive CSCs and promotes cell invasion through the PI3K/AKT pathway and also increases PCSCs enrichment by activating Focal Adhesion Kinase (FAK) [70]. Abnormal collagen cross-linking creates mechanical stresses that increase the rigidity and stiffness of the cancer matrix, which are important factors that are transmitted to CSC and regulate its proliferation and plasticity [71]. The ECM can also dynamically influence CSC ecology by creating a hypoxic environment [72]. 
Nevertheless, proteoglycans bind to various cytokines and chemokines in the tumor microenvironment to activate multiple signaling pathways in CSCs, including Notch, Wnt, and Hedgehog [73]. Transcriptional activation, mediated by the Wnt/β-catenin signaling pathway, induces the expression of C-MYC and SOX2, thereby promoting cancer stemness [74]. Glypican-4 (GPC4), as a typical proteoglycan, is associated with various human malignancies [75][76]. In addition, hyaluronic acid is a major ECM component of the stem cell niche, is frequently overexpressed in PDAC, and affects stromal cell behavior, which provides a favorable microenvironment for CSC self-renewal and maintenance [77]. This process mainly relies on the interaction of hyaluronic acid with its main receptor CD44. The hyaluronic acid-CD44 axis modulates the stemness properties of CSCs by inducing the EMT program and the secretion of extracellular vesicles. Specifically, excessive hyaluronic acid can activate AKT and ERK1/2 to induce EMT, and CD44 was found to be an important factor in TGF-β-induced EMT [78]. Intracellular hyaluronic acid-induced EMT increases centrosome abnormalities and micronucleation, creating a suitable niche for CSCs [79].

4. ECM, PCSCs, and Metastasis

PCSCs, one of the main forces that are responsible for cancer metastasis, have the ability to evade treatment, exosmosis, and colonization from the primary tumor site to the site of secondary metastasis [80]. The niche formation of the metastatic site drives the transfer of CSCs [7]. Interactions between CSCs and the microenvironment such as CAFs and immune cells, as well as with the cell matrix, contribute to CSC migration and the priming of metastatic sites [7]. Another major factor in the formation of metastatic niches is the presence of extracellular vesicles, which are exosomes that also contain ECM regulatory genes [71]. The cross-linking of collagen and elastin in the ECM is primarily regulated by the LOX protein family, which consists of LOX-1 and four related enzymes, LOX -like protein (LOXL1-4) [81][82][83]. LOXL2, in particular, leads to the stiffening of PDAC tissues by promoting the cross-linking of collagen fibers, and increases the secretion of related factors (such as exosomes) in primary tumor tissues, which leads to ECM remodeling or stromal cell recruitment, and promotes the formation of an ecological niche before secondary organ metastasis, and ultimately promotes metastatic formation [84]. Furthermore, the overexpression of LOXL2 in mouse models increases EMT and stemness, thereby promoting primary and metastatic tumor growth and reducing the overall survival [84].
Some specific ECM molecules, including hyaluronic acid and Tenascin-C, have become the focus of research on the mechanism of tumor metastasis to specific sites [85][86]. CD44, a PCSC marker, has been identified as a Hyaluronic acid receptor that activates the EMT pathway and promotes pancreatic cancer metastasis [86]. Tenascin-C enhances the expression of stem cell signaling components musashi homolog 1 (MSI1) and leucine-rich repeat G protein-coupled receptor 5 (LGR5). These molecules are positive regulators of the Notch signaling and target genes of the Wnt pathway, respectively, and promote the formation and growth of metastases [85]. The ECM components and their biological and physical properties are involved in the regulation of basic functions of immune cells, such as activation, proliferation and migration. The previously described M2 macrophages engineered with CAFs can drive cancer cell invasion in a CCL18-dependent manner [87]. Cytotoxic T-lymphocytes (CTLs) physiologically play an important role in eliminating cancer cells, but studies have found that they are often trapped in dense ECM compartments. Immune cells that are initially attracted to the tumor site by chemokines are prevented from migrating to the tumor core following contact with the area of increased stiffness [88][89]. Continuous ECM remodeling and overexpression of certain matrix components also promoted the recruitment of bone marrow cells, which are ultimately polarized to support ECM remodeling, CTL inhibition, tumor proliferation, and invasion [90][91].
The process of CSC migration involves ECM degradation, remodeling of cell–cell and cell–ECM interactions, formation of adhesive plaques and invasiveness, and EMT transformation, which requires a lot of cellular energy [92]. The glycolysis dependence of CSCs can drive the degradation of the ECM, the formation of invasive structures, and cellular protrusions, leading to the migration and invasion of cancer cells [93]. 
The YAP/TAZ transcriptional coactivator is a core component of the Hippo pathway and a sensor of the structural and mechanical characteristics of the cellular microenvironment [94]. Increased matrix stiffness in PDAC leads to YAP/TAZ activation, which in turn promotes the production of profibrotic mediators and ECM proteins. Activated YAP/TAZ can enhance tumor proliferation and survival by transactivating target genes that are related to cell cycle progression and anti-apoptosis and can also induce the expression of the proto-oncogene c-Myc to promote cell cycle progression [95][96]. More importantly, YAP/TAZ is closely related to ZEB1/2 and Twist, both of which can be used to regulate EMT, thereby inducing malignant features of cancer cells and CSC-related properties, such as tumor initiation, drug resistance, and metastasis [97]. 

5. ECM, PCSCs, and Chemoresistance

To date, the mechanisms of ECM-related chemoresistance have been identified, which can be roughly divided into two major categories, namely physical barriers (abnormal vascularization and matrix stiffness) and cell adhesion-related means (ECM tissue, mechanical signaling pathways, and pro-survival signaling pathways) [98] (Figure 1). Aberrant ECM remodeling results in increased matrix stiffness, vessel collapse, and reduced blood flow, which greatly reduces the ability of drugs to enter the tumor [99]. As previously described, dense fibrosis and abnormal vascularization in PDAC contribute to the formation of a hypoxic and pH-abnormal tumor microenvironment. Hypoxia also affects drug movement from the bloodstream to the tumor microenvironment, specifically affecting the activity of drug transporters and the expression and activity of phase I drug metabolizing enzymes [100][101][102]. Glycolysis under hypoxia results in the production of large amounts of lactic acid, which reduces the extracellular pH. The ability of the drug to cross the hydrophobic membrane is greatly reduced when the drug is electrically charged in an acidic environment [100]. In addition to the dense fibrotic ECM that impairs the ability of drugs to spread from blood vessels to cancer cells, most ECM proteins contribute to chemoresistance by activating EMT and oncogenic signaling pathways, including MAPK, PI3K, and YAP [103][104][105][106]. CSCs are also an important factor leading to chemotherapy resistance, but there are only few studies that are available on the relationship between the ECM and PCSC in chemoresistance. 
Figure 1. Signaling pathways that are associated with matrix stiffness. Matrix stiffness activates a large number of mechano-responsive signaling pathways in different cells through integrins, ion channels, and other transmembrane proteins. Pathways such as PI3K, RhoA-ROCK, and YAP/TAZ play major roles in this conduction. The central players in these signaling pathways can be connected to other molecules to eventually transform the changes in the ECM into related biological changes and phenotypes.
Cytotoxic agents have been the cornerstone of chemotherapy for PDAC, but more studies are needed to understand their effects on ECM dynamics and CSCs-acquired chemotherapy resistance. Recent studies have shown that the abnormal expression and activation of the transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) and its major negative regulator Kelch-like ECH-associated protein 1 (Keap1) are observed at different stages of PDAC, and are involved in tumor development, metastasis, and drug resistance [107][108]. During PDAC progression and metastasis, Keap1 is frequently mutated and silenced, resulting in abnormal stabilization of NRF2 [108]. NRF2 can be activated by stromal-derived factor 1α (SDF-1α) and IL-6, that are secreted by PSCs [109]. The activation of NRF2 can induce drug resistance of CSCs through the up-regulation of glutathione pathway. The activation of the glutathione pathway involves binding of TGF-β to its membrane receptor, followed by upregulation of P21. CSCs cell cycles that respond to TGF-β are slowed-down or stopped, which contributes to chemotherapy resistance because cytotoxic chemotherapy induces apoptosis by causing DNA damage exclusively in rapidly dividing cells [110][111].

6. Pharmacological Targeting of ECM

Collagen is one of the most basic components in the ECM, and it is also one of the ideal therapeutic directions. TGF-β plays a key role in collagen synthesis, so TGF-β signaling is the most promising target for inhibiting collagen synthesis. In animal models of PDAC, an anticoccidial named halofuginone has been shown to reduce collagen synthesis by inhibiting TGF-β signaling [112]. TGF-β is usually overexpressed in PDAC and blocking TGF-β-mediated signaling may enhance antitumor effects [110][111]. A clinical trial aiming to target TGF-β in PDAC is investigating the antitumor activity of SAR439459, a pan-TGF-β neutralizing antibody [113]. Vitamin D may also block collagen secretion by disrupting the TGF-β signaling pathway, helping to prevent tumor metastasis and enhance drug responses [114][115]. The inhibition of collagen cross-linking is also a therapeutic strategy to target ECM stiffness in cancer. In 2017, a randomized Phase II study of Simtuzumab, a humanized IgG4 monoclonal antibody that inhibits extracellular LOXL2, was performed in combination with gemcitabine in patients that were suffering from metastatic PDAC [84]. However, the results showed that a combination of gemcitabine and Simtuzumab did not improve clinical outcomes. Therefore, the complex tumor-stromal interaction of LOXL2 in PDAC tumorigenesis requires further investigation and re-evaluation of the efficacy of using anti-LOXL2 antibodies or small molecule LOXL2 inhibitors in the treatment landscape of metastatic PDAC [116].

There are other therapeutic ideas aiming to target the MMP to alter ECM stiffness. For example, MMP-9 promotes aggressive and metastatic phenotypes in tumor cells, and its overexpression increases the aggressiveness of cancer cell lines in vitro [117]. Targeting integrin-mediated signaling is another strategy for ECM therapy. In theory, it is possible to disrupt signals from the extracellular or intracellular environment by using integrin inhibitors to disrupt ECM mechanical sensing [118]. Targeted glutamine metabolism and hexosamine biosynthesis pathways has been shown to have profound effects on the ECM and CSC self-renewal of PDAC among metabolic inhibitors [119].

Clinical trials involving different inhibitors are being conducted in different clinical settings, primarily for ECM-induced stemness of PCSCs. For example, the inhibitors of Rho-associated kinase (ROCK) alter the contractility of PDAC cytoskeleton and CAF, may benefit drug delivery and inhibit metastasis. ECM disorder occurrence and PDAC migration and invasion are prevented when ROCK is suppressed. Other mouse models showed that a pre-chemotherapy administration of ROCK inhibitors increased the chemotherapy response of the primary tumor and helped to prevent the development of liver metastases [120][121][122]. T13148 was the first ROCK inhibitor that was investigated for the treatment of solid tumors, but further development of this compound is advised due to drug side effects [123].

References

  1. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33.
  2. Cronin, K.A.; Lake, A.J.; Scott, S.; Sherman, R.L.; Noone, A.M.; Howlader, N.; Henley, S.J.; Anderson, R.N.; Firth, A.U.; Ma, J.; et al. Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics. Cancer 2018, 124, 2785–2800.
  3. Sally, A.; McGowan, R.; Finn, K.; Moran, B.M. Current and Future Therapies for Pancreatic Ductal Adenocarcinoma. Cancers 2022, 14, 2417.
  4. Güngör, C.; Hofmann, B.T.; Wolters-Eisfeld, G.; Bockhorn, M. Pancreatic cancer. Br. J. Pharmacol. 2014, 171, 849–858.
  5. Balaban, E.P.; Mangu, P.B.; Khorana, A.A.; Shah, M.A.; Mukherjee, S.; Crane, C.H.; Javle, M.M.; Eads, J.R.; Allen, P.; Ko, A.H.; et al. Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 2016, 34, 2654–2668.
  6. Golan, T.; Hammel, P.; Reni, M.; Van Cutsem, E.; Macarulla, T.; Hall, M.J.; Park, J.O.; Hochhauser, D.; Arnold, D.; Oh, D.Y.; et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N. Engl. J. Med. 2019, 381, 317–327.
  7. Kai, F.; Drain, A.P.; Weaver, V.M. The Extracellular Matrix Modulates the Metastatic Journey. Dev. Cell 2019, 49, 332–346.
  8. Yeldag, G.; Rice, A.; Del Rio Hernandez, A. Chemoresistance and the Self-Maintaining Tumor Microenvironment. Cancers 2018, 10, 471.
  9. Humphrey, J.D.; Dufresne, E.R.; Schwartz, M.A. Mechanotransduction and extracellular matrix homeostasis. Nat. Rev. Mol. Cell Biol. 2014, 15, 802–812.
  10. Hellewell, A.L.; Adams, J.C. Insider trading: Extracellular matrix proteins and their non-canonical intracellular roles. Bioessays 2016, 38, 77–88.
  11. Mecham, R.P. Overview of extracellular matrix. Curr. Protoc. Cell Biol. 2012, 57, 10.1.1–10.1.16.
  12. Venning, F.A.; Wullkopf, L.; Erler, J.T. Targeting ECM Disrupts Cancer Progression. Front. Oncol. 2015, 5, 224.
  13. Acerbi, I.; Cassereau, L.; Dean, I.; Shi, Q.; Au, A.; Park, C.; Chen, Y.Y.; Liphardt, J.; Hwang, E.S.; Weaver, V.M. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr. Biol. 2015, 7, 1120–1134.
  14. Tian, C.; Ohlund, D.; Rickelt, S.; Lidstrom, T.; Huang, Y.; Hao, L.; Zhao, R.T.; Franklin, O.; Bhatia, S.N.; Tuveson, D.A.; et al. Cancer Cell-Derived Matrisome Proteins Promote Metastasis in Pancreatic Ductal Adenocarcinoma. Cancer Res. 2020, 80, 1461–1474.
  15. Jacobetz, M.A.; Chan, D.S.; Neesse, A.; Bapiro, T.E.; Cook, N.; Frese, K.K.; Feig, C.; Nakagawa, T.; Caldwell, M.E.; Zecchini, H.I.; et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 2013, 62, 112–120.
  16. Bonnans, C.; Chou, J.; Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 2014, 15, 786–801.
  17. Huang, J.; Zhang, L.; Wan, D.; Zhou, L.; Zheng, S.; Lin, S.; Qiao, Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct. Target. Ther. 2021, 6, 153.
  18. Walker, C.; Mojares, E.; Del Rio Hernandez, A. Role of Extracellular Matrix in Development and Cancer Progression. Int. J. Mol. Sci. 2018, 19, 3028.
  19. Kessenbrock, K.; Plaks, V.; Werb, Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 2010, 141, 52–67.
  20. Sun, Q.; Zhang, B.; Hu, Q.; Qin, Y.; Xu, W.; Liu, W.; Yu, X.; Xu, J. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics 2018, 8, 5072–5087.
  21. Jamin, Y.; Boult, J.K.R.; Li, J.; Popov, S.; Garteiser, P.; Ulloa, J.L.; Cummings, C.; Box, G.; Eccles, S.A.; Jones, C.; et al. Exploring the biomechanical properties of brain malignancies and their pathologic determinants in vivo with magnetic resonance elastography. Cancer Res. 2015, 75, 1216–1224.
  22. Hu, G.; Xu, F.; Zhong, K.; Wang, S.; Huang, L.; Chen, W. Activated Tumor-infiltrating Fibroblasts Predict Worse Prognosis in Breast Cancer Patients. J. Cancer 2018, 9, 3736–3742.
  23. Ohlund, D.; Elyada, E.; Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 2014, 211, 1503–1523.
  24. Neuzillet, C.; Tijeras-Raballand, A.; Ragulan, C.; Cros, J.; Patil, Y.; Martinet, M.; Erkan, M.; Kleeff, J.; Wilson, J.; Apte, M.; et al. Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J. Pathol. 2019, 248, 51–65.
  25. Lambert, A.; Schwarz, L.; Borbath, I.; Henry, A.; Van Laethem, J.L.; Malka, D.; Ducreux, M.; Conroy, T. An update on treatment options for pancreatic adenocarcinoma. Ther. Adv. Med. Oncol. 2019, 11, 1758835919875568.
  26. Apte, M.V.; Xu, Z.; Pothula, S.; Goldstein, D.; Pirola, R.C.; Wilson, J.S. Pancreatic cancer: The microenvironment needs attention too! Pancreatology 2015, 15, S32–S38.
  27. Xu, Z.; Pothula, S.P.; Wilson, J.S.; Apte, M.V. Pancreatic cancer and its stroma: A conspiracy theory. World J. Gastroenterol. 2014, 20, 11216–11229.
  28. Arina, A.; Idel, C.; Hyjek, E.M.; Alegre, M.L.; Wang, Y.; Bindokas, V.P.; Weichselbaum, R.R.; Schreiber, H. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc. Natl. Acad. Sci. USA 2016, 113, 7551–7556.
  29. Liu, T.; Han, C.; Wang, S.; Fang, P.; Ma, Z.; Xu, L.; Yin, R. Cancer-associated fibroblasts: An emerging target of anti-cancer immunotherapy. J. Hematol. Oncol. 2019, 12, 86.
  30. Norton, J.; Foster, D.; Chinta, M.; Titan, A.; Longaker, M. Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment. Cancers 2020, 12, 1347.
  31. Huang, T.X.; Guan, X.Y.; Fu, L. Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells. Am. J. Cancer Res. 2019, 9, 1889–1904.
  32. Elyada, E.; Bolisetty, M.; Laise, P.; Flynn, W.F.; Courtois, E.T.; Burkhart, R.A.; Teinor, J.A.; Belleau, P.; Biffi, G.; Lucito, M.S.; et al. Cross-Species Single-Cell Analysis of Pancreatic Ductal Adenocarcinoma Reveals Antigen-Presenting Cancer-Associated Fibroblasts. Cancer Discov. 2019, 9, 1102–1123.
  33. Lu, P.; Takai, K.; Weaver, V.M.; Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 2011, 3, a005058.
  34. Egeblad, M.; Nakasone, E.S.; Werb, Z. Tumors as organs: Complex tissues that interface with the entire organism. Dev. Cell 2010, 18, 884–901.
  35. Egeblad, M.; Rasch, M.G.; Weaver, V.M. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 2010, 22, 697–706.
  36. Craven, K.E.; Gore, J.; Korc, M. Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma. Cancer Lett. 2016, 381, 201–210.
  37. Fukumura, D.; Jain, R.K. Imaging angiogenesis and the microenvironment. APMIS 2008, 116, 695–715.
  38. Chomarat, P.; Banchereau, J.; Davoust, J.; Palucka, A.K. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat. Immunol. 2000, 1, 510–514.
  39. Chen, W.; Jin, W.; Hardegen, N.; Lei, K.J.; Li, L.; Marinos, N.; McGrady, G.; Wahl, S.M. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J. Exp. Med. 2003, 198, 1875–1886.
  40. Nielsen, M.F.; Mortensen, M.B.; Detlefsen, S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J. Gastroenterol. 2016, 22, 2678–2700.
  41. Bachem, M.G.; Schunemann, M.; Ramadani, M.; Siech, M.; Beger, H.; Buck, A.; Zhou, S.; Schmid-Kotsas, A.; Adler, G. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 2005, 128, 907–921.
  42. Tian, C.; Clauser, K.R.; Ohlund, D.; Rickelt, S.; Huang, Y.; Gupta, M.; Mani, D.R.; Carr, S.A.; Tuveson, D.A.; Hynes, R.O. Proteomic analyses of ECM during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc. Natl. Acad. Sci. USA 2019, 116, 19609–19618.
  43. Naba, A.; Clauser, K.R.; Ding, H.; Whittaker, C.A.; Carr, S.A.; Hynes, R.O. The extracellular matrix: Tools and insights for the “omics” era. Matrix Biol. 2016, 49, 10–24.
  44. Ohtsubo, K.; Marth, J.D. Glycosylation in cellular mechanisms of health and disease. Cell 2006, 126, 855–867.
  45. Yang, C.; Liu, Z.; Zeng, X.; Wu, Q.; Liao, X.; Wang, X.; Han, C.; Yu, T.; Zhu, G.; Qin, W.; et al. Evaluation of the diagnostic ability of laminin gene family for pancreatic ductal adenocarcinoma. Aging 2019, 11, 3679–3703.
  46. Katayama, M.; Sekiguchi, K. Laminin-5 in epithelial tumour invasion. J. Mol. Histol. 2004, 35, 277–286.
  47. Wang, H.; Fu, W.; Im, J.H.; Zhou, Z.; Santoro, S.A.; Iyer, V.; DiPersio, C.M.; Yu, Q.C.; Quaranta, V.; Al-Mehdi, A.; et al. Tumor cell alpha3beta1 integrin and vascular laminin-5 mediate pulmonary arrest and metastasis. J. Cell Biol. 2004, 164, 935–941.
  48. Ortiz-Urda, S.; Garcia, J.; Green, C.L.; Chen, L.; Lin, Q.; Veitch, D.P.; Sakai, L.Y.; Lee, H.; Marinkovich, M.P.; Khavari, P.A. Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science 2005, 307, 1773–1776.
  49. To, W.S.; Midwood, K.S. Plasma and cellular fibronectin: Distinct and independent functions during tissue repair. Fibrogenes. Tissue Repair 2011, 4, 21.
  50. Zeltz, C.; Orgel, J.; Gullberg, D. Molecular composition and function of integrin-based collagen glues-introducing COLINBRIs. Biochim. Biophys. Acta 2014, 1840, 2533–2548.
  51. Miyamoto, H.; Murakami, T.; Tsuchida, K.; Sugino, H.; Miyake, H.; Tashiro, S. Tumor-stroma interaction of human pancreatic cancer: Acquired resistance to anticancer drugs and proliferation regulation is dependent on extracellular matrix proteins. Pancreas 2004, 28, 38–44.
  52. Orozco, C.A.; Martinez-Bosch, N.; Guerrero, P.E.; Vinaixa, J.; Dalotto-Moreno, T.; Iglesias, M.; Moreno, M.; Djurec, M.; Poirier, F.; Gabius, H.J.; et al. Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc. Natl. Acad. Sci. USA 2018, 115, E3769–E3778.
  53. Chen, R.; Dawson, D.W.; Pan, S.; Ottenhof, N.A.; de Wilde, R.F.; Wolfgang, C.L.; May, D.H.; Crispin, D.A.; Lai, L.A.; Lay, A.R.; et al. Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma. Lab. Investig. 2015, 95, 43–55.
  54. Astorgues-Xerri, L.; Riveiro, M.E.; Tijeras-Raballand, A.; Serova, M.; Neuzillet, C.; Albert, S.; Raymond, E.; Faivre, S. Unraveling galectin-1 as a novel therapeutic target for cancer. Cancer Treat. Rev. 2014, 40, 307–319.
  55. Theocharis, A.D.; Tsara, M.E.; Papageorgacopoulou, N.; Karavias, D.D.; Theocharis, D.A. Pancreatic carcinoma is characterized by elevated content of hyaluronan and chondroitin sulfate with altered disaccharide composition. Biochim. Biophys. Acta 2000, 1502, 201–206.
  56. Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; Von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21, 418–429.
  57. Goossens, P.; Rodriguez-Vita, J.; Etzerodt, A.; Masse, M.; Rastoin, O.; Gouirand, V.; Ulas, T.; Papantonopoulou, O.; Van Eck, M.; Auphan-Anezin, N.; et al. Membrane Cholesterol Efflux Drives Tumor-Associated Macrophage Reprogramming and Tumor Progression. Cell Metab. 2019, 29, 1376–1389.e4.
  58. Mahlbacher, V.; Sewing, A.; Elsasser, H.P.; Kern, H.F. Hyaluronan is a secretory product of human pancreatic adenocarcinoma cells. Eur. J. Cell Biol. 1992, 58, 28–34.
  59. Sullivan, W.J.; Mullen, P.J.; Schmid, E.W.; Flores, A.; Momcilovic, M.; Sharpley, M.S.; Jelinek, D.; Whiteley, A.E.; Maxwell, M.B.; Wilde, B.R.; et al. Extracellular Matrix Remodeling Regulates Glucose Metabolism through TXNIP Destabilization. Cell 2018, 175, 117–132.e21.
  60. Apte, M.V.; Pirola, R.C.; Wilson, J.S. Pancreatic stellate cells: A starring role in normal and diseased pancreas. Front. Physiol. 2012, 3, 344.
  61. Shen, W.; Tao, G.Q.; Zhang, Y.; Cai, B.; Sun, J.; Tian, Z.Q. TGF-beta in pancreatic cancer initiation and progression: Two sides of the same coin. Cell Biosci. 2017, 7, 39.
  62. Perez, V.M.; Kearney, J.F.; Yeh, J.J. The PDAC Extracellular Matrix: A Review of the ECM Protein Composition, Tumor Cell Interaction, and Therapeutic Strategies. Front. Oncol. 2021, 11, 751311.
  63. Paszek, M.J.; Zahir, N.; Johnson, K.R.; Lakins, J.N.; Rozenberg, G.I.; Gefen, A.; Reinhart-King, C.A.; Margulies, S.S.; Dembo, M.; Boettiger, D.; et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005, 8, 241–254.
  64. Cox, T.R.; Bird, D.; Baker, A.M.; Barker, H.E.; Ho, M.W.; Lang, G.; Erler, J.T. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 2013, 73, 1721–1732.
  65. Lee, J.; Condello, S.; Yakubov, B.; Emerson, R.; Caperell-Grant, A.; Hitomi, K.; Xie, J.; Matei, D. Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression. Clin. Cancer Res. 2015, 21, 4482–4493.
  66. Rice, A.J.; Cortes, E.; Lachowski, D.; Cheung, B.C.H.; Karim, S.A.; Morton, J.P.; Del Rio Hernandez, A. Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis 2017, 6, e352.
  67. Haage, A.; Schneider, I.C. Cellular contractility and extracellular matrix stiffness regulate matrix metalloproteinase activity in pancreatic cancer cells. FASEB J. 2014, 28, 3589–3599.
  68. Li, C.; Heidt, D.G.; Dalerba, P.; Burant, C.F.; Zhang, L.; Adsay, V.; Wicha, M.; Clarke, M.F.; Simeone, D.M. Identification of pancreatic cancer stem cells. Cancer Res. 2007, 67, 1030–1037.
  69. Medema, J.P. Cancer stem cells: The challenges ahead. Nat. Cell Biol. 2013, 15, 338–344.
  70. Motegi, H.; Kamoshima, Y.; Terasaka, S.; Kobayashi, H.; Houkin, K. Type 1 collagen as a potential niche component for CD133-positive glioblastoma cells. Neuropathology 2014, 34, 378–385.
  71. Kesh, K.; Gupta, V.K.; Durden, B.; Garrido, V.; Mateo-Victoriano, B.; Lavania, S.P.; Banerjee, S. Therapy Resistance, Cancer Stem Cells and ECM in Cancer: The Matrix Reloaded. Cancers 2020, 12, 3067.
  72. Grassian, A.R.; Coloff, J.L.; Brugge, J.S. Extracellular matrix regulation of metabolism and implications for tumorigenesis. Cold Spring Harb. Symp. Quant. Biol. 2011, 76, 313–324.
  73. Vitale, D.; Kumar Katakam, S.; Greve, B.; Jang, B.; Oh, E.S.; Alaniz, L.; Gotte, M. Proteoglycans and glycosaminoglycans as regulators of cancer stem cell function and therapeutic resistance. FEBS J. 2019, 286, 2870–2882.
  74. Wu, C.; Zhang, H.F.; Gupta, N.; Alshareef, A.; Wang, Q.; Huang, Y.H.; Lewis, J.T.; Douglas, D.N.; Kneteman, N.M.; Lai, R. A positive feedback loop involving the Wnt/beta-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma. J. Hematol. Oncol. 2016, 9, 120.
  75. Munir, J.; Van Ngu, T.; Na Ayudthaya, P.D.; Ryu, S. Downregulation of glypican-4 facilitates breast cancer progression by inducing cell migration and proliferation. Biochem. Biophys. Res. Commun. 2020, 526, 91–97.
  76. Zhao, D.; Liu, S.; Sun, L.; Zhao, Z.; Liu, S.; Kuang, X.; Shu, J.; Luo, B. Glypican-4 gene polymorphism (rs1048369) and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma. Virus Res. 2016, 220, 52–56.
  77. Skandalis, S.S.; Karalis, T.T.; Chatzopoulos, A.; Karamanos, N.K. Hyaluronan-CD44 axis orchestrates cancer stem cell functions. Cell. Signal. 2019, 63, 109377.
  78. Porsch, H.; Bernert, B.; Mehic, M.; Theocharis, A.D.; Heldin, C.H.; Heldin, P. Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. Oncogene 2013, 32, 4355–4365.
  79. Preca, B.T.; Bajdak, K.; Mock, K.; Sundararajan, V.; Pfannstiel, J.; Maurer, J.; Wellner, U.; Hopt, U.T.; Brummer, T.; Brabletz, S.; et al. A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells. Int. J. Cancer 2015, 137, 2566–2577.
  80. Steinbichler, T.B.; Savic, D.; Dudas, J.; Kvitsaridze, I.; Skvortsov, S.; Riechelmann, H.; Skvortsova, I.I. Cancer stem cells and their unique role in metastatic spread. Semin. Cancer Biol. 2020, 60, 148–156.
  81. Kim, Y.M.; Kim, E.C.; Kim, Y. The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin. Mol. Biol. Rep. 2011, 38, 145–149.
  82. Moon, H.J.; Finney, J.; Ronnebaum, T.; Mure, M. Human lysyl oxidase-like 2. Bioorg. Chem. 2014, 57, 231–241.
  83. Cano, A.; Santamaria, P.G.; Moreno-Bueno, G. LOXL2 in epithelial cell plasticity and tumor progression. Future Oncol. 2012, 8, 1095–1108.
  84. Alonso-Nocelo, M.; Ruiz-Canas, L.; Sancho, P.; Gorgulu, K.; Alcala, S.; Pedrero, C.; Vallespinos, M.; Lopez-Gil, J.C.; Ochando, M.; Garcia-Garcia, E.; et al. Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma. Gut 2022.
  85. Oskarsson, T.; Acharyya, S.; Zhang, X.H.; Vanharanta, S.; Tavazoie, S.F.; Morris, P.G.; Downey, R.J.; Manova-Todorova, K.; Brogi, E.; Massague, J. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat. Med. 2011, 17, 867–874.
  86. Jiang, W.; Zhang, Y.; Kane, K.T.; Collins, M.A.; Simeone, D.M.; di Magliano, M.P.; Nguyen, K.T. CD44 regulates pancreatic cancer invasion through MT1-MMP. Mol. Cancer Res. 2015, 13, 9–15.
  87. Pinto, M.L.; Rios, E.; Silva, A.C.; Neves, S.C.; Caires, H.R.; Pinto, A.T.; Duraes, C.; Carvalho, F.A.; Cardoso, A.P.; Santos, N.C.; et al. Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18. Biomaterials 2017, 124, 211–224.
  88. Salmon, H.; Franciszkiewicz, K.; Damotte, D.; Dieu-Nosjean, M.C.; Validire, P.; Trautmann, A.; Mami-Chouaib, F.; Donnadieu, E. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Investig. 2012, 122, 899–910.
  89. Henke, E.; Nandigama, R.; Ergun, S. Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy. Front. Mol. Biosci. 2019, 6, 160.
  90. Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253–268.
  91. Liguori, M.; Solinas, G.; Germano, G.; Mantovani, A.; Allavena, P. Tumor-associated macrophages as incessant builders and destroyers of the cancer stroma. Cancers 2011, 3, 3740–3761.
  92. Elia, I.; Doglioni, G.; Fendt, S.M. Metabolic Hallmarks of Metastasis Formation. Trends Cell Biol. 2018, 28, 673–684.
  93. Attanasio, F.; Caldieri, G.; Giacchetti, G.; van Horssen, R.; Wieringa, B.; Buccione, R. Novel invadopodia components revealed by differential proteomic analysis. Eur. J. Cell Biol. 2011, 90, 115–127.
  94. Piccolo, S.; Dupont, S.; Cordenonsi, M. The biology of YAP/TAZ: Hippo signaling and beyond. Physiol. Rev. 2014, 94, 1287–1312.
  95. Di Agostino, S.; Sorrentino, G.; Ingallina, E.; Valenti, F.; Ferraiuolo, M.; Bicciato, S.; Piazza, S.; Strano, S.; Del Sal, G.; Blandino, G. YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins. EMBO Rep. 2016, 17, 188–201.
  96. Zanconato, F.; Forcato, M.; Battilana, G.; Azzolin, L.; Quaranta, E.; Bodega, B.; Rosato, A.; Bicciato, S.; Cordenonsi, M.; Piccolo, S. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat. Cell Biol. 2015, 17, 1218–1227.
  97. Noguchi, S.; Saito, A.; Nagase, T. YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer. Int. J. Mol. Sci. 2018, 19, 3674.
  98. Holle, A.W.; Young, J.L.; Spatz, J.P. In vitro cancer cell-ECM interactions inform in vivo cancer treatment. Adv. Drug Deliv. Rev. 2016, 97, 270–279.
  99. Zhang, B.; Wang, H.; Jiang, T.; Jin, K.; Luo, Z.; Shi, W.; Mei, H.; Wang, H.; Hu, Y.; Pang, Z.; et al. Cyclopamine treatment disrupts extracellular matrix and alleviates solid stress to improve nanomedicine delivery for pancreatic cancer. J. Drug Target. 2018, 26, 913–919.
  100. Sriraman, S.K.; Aryasomayajula, B.; Torchilin, V.P. Barriers to drug delivery in solid tumors. Tissue Barriers 2014, 2, e29528.
  101. Du Souich, P.; Fradette, C. The effect and clinical consequences of hypoxia on cytochrome P450, membrane carrier proteins activity and expression. Expert Opin. Drug Metab. Toxicol. 2011, 7, 1083–1100.
  102. Comerford, K.M.; Wallace, T.J.; Karhausen, J.; Louis, N.A.; Montalto, M.C.; Colgan, S.P. Hypoxia-inducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene. Cancer Res. 2002, 62, 3387–3394.
  103. Weniger, M.; Honselmann, K.C.; Liss, A.S. The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship. Cancers 2018, 10, 316.
  104. Slack-Davis, J.K.; Eblen, S.T.; Zecevic, M.; Boerner, S.A.; Tarcsafalvi, A.; Diaz, H.B.; Marshall, M.S.; Weber, M.J.; Parsons, J.T.; Catling, A.D. PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J. Cell Biol. 2003, 162, 281–291.
  105. Yousif, N.G. Fibronectin promotes migration and invasion of ovarian cancer cells through up-regulation of FAK-PI3K/Akt pathway. Cell Biol. Int. 2014, 38, 85–91.
  106. Kim, N.G.; Gumbiner, B.M. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J. Cell Biol. 2015, 210, 503–515.
  107. Lister, A.; Nedjadi, T.; Kitteringham, N.R.; Campbell, F.; Costello, E.; Lloyd, B.; Copple, I.M.; Williams, S.; Owen, A.; Neoptolemos, J.P.; et al. Nrf2 is overexpressed in pancreatic cancer: Implications for cell proliferation and therapy. Mol. Cancer 2011, 10, 37.
  108. Chio, I.I.C.; Jafarnejad, S.M.; Ponz-Sarvise, M.; Park, Y.; Rivera, K.; Palm, W.; Wilson, J.; Sangar, V.; Hao, Y.; Ohlund, D.; et al. NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Cell 2016, 166, 963–976.
  109. Wu, Y.S.; Looi, C.Y.; Subramaniam, K.S.; Masamune, A.; Chung, I. Soluble factors from stellate cells induce pancreatic cancer cell proliferation via Nrf2-activated metabolic reprogramming and ROS detoxification. Oncotarget 2016, 7, 36719–36732.
  110. Oshimori, N.; Oristian, D.; Fuchs, E. TGF-beta promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell 2015, 160, 963–976.
  111. Brown, J.A.; Yonekubo, Y.; Hanson, N.; Sastre-Perona, A.; Basin, A.; Rytlewski, J.A.; Dolgalev, I.; Meehan, S.; Tsirigos, A.; Beronja, S.; et al. TGF-beta-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma. Cell Stem Cell 2017, 21, 650–664.e8.
  112. Zion, O.; Genin, O.; Kawada, N.; Yoshizato, K.; Roffe, S.; Nagler, A.; Iovanna, J.L.; Halevy, O.; Pines, M. Inhibition of transforming growth factor beta signaling by halofuginone as a modality for pancreas fibrosis prevention. Pancreas 2009, 38, 427–435.
  113. Greco, R.; Qu, H.; Qu, H.; Theilhaber, J.; Shapiro, G.; Gregory, R.; Winter, C.; Malkova, N.; Sun, F.; Jaworski, J.; et al. Pan-TGFbeta inhibition by SAR439459 relieves immunosuppression and improves antitumor efficacy of PD-1 blockade. Oncoimmunology 2020, 9, 1811605.
  114. Shany, S.; Sigal-Batikoff, I.; Lamprecht, S. Vitamin D and Myofibroblasts in Fibrosis and Cancer: At Cross-purposes with TGF-beta/SMAD Signaling. Anticancer Res. 2016, 36, 6225–6234.
  115. Artaza, J.N.; Norris, K.C. Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells. J. Endocrinol. 2009, 200, 207–221.
  116. Chang, J.; Lucas, M.C.; Leonte, L.E.; Garcia-Montolio, M.; Singh, L.B.; Findlay, A.D.; Deodhar, M.; Foot, J.S.; Jarolimek, W.; Timpson, P.; et al. Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer. Oncotarget 2017, 8, 26066–26078.
  117. Plaks, V.; Kong, N.; Werb, Z. The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 2015, 16, 225–238.
  118. Rezza, A.; Sennett, R.; Rendl, M. Adult stem cell niches: Cellular and molecular components. Curr. Top. Dev. Biol. 2014, 107, 333–372.
  119. Sharma, N.S.; Gupta, V.K.; Garrido, V.T.; Hadad, R.; Durden, B.C.; Kesh, K.; Giri, B.; Ferrantella, A.; Dudeja, V.; Saluja, A.; et al. Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy. J. Clin. Investig. 2020, 130, 451–465.
  120. Vennin, C.; Chin, V.T.; Warren, S.C.; Lucas, M.C.; Herrmann, D.; Magenau, A.; Melenec, P.; Walters, S.N.; Del Monte-Nieto, G.; Conway, J.R.; et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci. Transl. Med. 2017, 9, eaai8504.
  121. Rath, N.; Munro, J.; Cutiongco, M.F.; Jagiello, A.; Gadegaard, N.; McGarry, L.; Unbekandt, M.; Michalopoulou, E.; Kamphorst, J.J.; Sumpton, D.; et al. Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth. Cancer Res. 2018, 78, 3321–3336.
  122. Vennin, C.; Rath, N.; Pajic, M.; Olson, M.F.; Timpson, P. Targeting ROCK activity to disrupt and prime pancreatic cancer for chemotherapy. Small GTPases 2020, 11, 45–52.
  123. McLeod, R.; Kumar, R.; Papadatos-Pastos, D.; Mateo, J.; Brown, J.S.; Garces, A.H.I.; Ruddle, R.; Decordova, S.; Jueliger, S.; Ferraldeschi, R.; et al. First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors. Clin. Cancer Res. 2020, 26, 4777–4784.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Dan Wang
,
Yuqiang Li
,
Heming Ge
,
Tarik Ghadban
,
Matthias Reeh
,
Cenap Güngör
View Times: 333
Revisions: 2 times (View History)
Update Date: 02 Sep 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback