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Fedele, M.; Cerchia, L.; Sgarra, R. Proneural-Mesenchymal Transition. Encyclopedia. Available online: https://encyclopedia.pub/entry/17048 (accessed on 27 July 2024).
Fedele M, Cerchia L, Sgarra R. Proneural-Mesenchymal Transition. Encyclopedia. Available at: https://encyclopedia.pub/entry/17048. Accessed July 27, 2024.
Fedele, Monica, Laura Cerchia, Riccardo Sgarra. "Proneural-Mesenchymal Transition" Encyclopedia, https://encyclopedia.pub/entry/17048 (accessed July 27, 2024).
Fedele, M., Cerchia, L., & Sgarra, R. (2021, December 13). Proneural-Mesenchymal Transition. In Encyclopedia. https://encyclopedia.pub/entry/17048
Fedele, Monica, et al. "Proneural-Mesenchymal Transition." Encyclopedia. Web. 13 December, 2021.
Proneural-Mesenchymal Transition
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This entry is adapted from the peer-reviewed paper 10.3390/ijms20112746

Glioblastoma (GBM) is an extremely aggressive tumor of the central nervous system, with a prognosis of 12–15 months and just 3–5% of survival over 5 years. This is mainly because most patients suffer recurrence after treatment that currently consists in maximal resection followed by radio- and chemotherapy with temozolomide. GBM has been classified into four molecular subgroups namely proneural, neural, classical and mesenchymal. The recurrent tumor shows a more aggressive behavior due to a phenotypic shift from the proneural toward the mesenchymal subtype. Proneural-mesenchymal transition (PMT) may represent for GBM the equivalent of epithelial–mesenchymal transition associated with aggressive carcinomas. 

glioma proneural-mesenchymal transition (PMT) multitherapy resistance gliobalstoma phenotipic plasticity

1. Introduction

Glioblastoma (GBM) is the most common intrinsic and aggressive primary brain tumor in adults. It is characterized by alteration in crucial signaling pathways that results in the acquisition of hallmarks properties of cancer. Consequently, GBM exhibits a diffused infiltration throughout the brain rendering it incurable by surgery [1]. Since the 1970s, the first-line adjuvant treatment after surgery is represented by radiotherapy that has been recently been combined with targeted chemotherapy approaches involving DNA alkylating agents, such as temozolomide (TMZ). Unfortunately, this therapeutic option shows many limitations in its efficacy and almost all patients present the progression of the disease after a mean progression-free survival of 7–10 months [2][3]. Therefore, despite therapeutic strategies and supportive care having been improved, GBM remains characterized by a very poor quality of life and prognosis, with a mean median survival time of 15 months [2]. The poor outcome of GBM has been ascribed to the high degree of intra-tumor heterogeneity that occurs at multiple levels, including histopathological, transcriptional and genomic [4][5][6][7]. In the effort to facilitate the development of more effective target therapies, large-scale genomic projects on patient specimens have adopted to identify GBM molecular subtypes associated with prognostic values [8][9]. Ultimately, GBM has been classified into at least four molecular subgroups namely proneural (PN), neural (NL), classical (CL) and mesenchymal (MES) [9]. Since typical molecular alterations, sensitivity to therapy and prognosis are associated with each subgroup, this classification has implications in selecting target therapy strategies. The MES subtype is the most aggressive and strongly associated with a poor prognosis compared to PN subtype, in addition, a shift from PN to MES subtype, namely the PMT, can occur in patients following radiation therapy and chemotherapy [10]. The molecular events driving this transition are similar to those driving the epithelial-mesenchymal transition (EMT) in carcinomas cells. EMT has been described as a crucial mechanism by which carcinoma cells enhance their invasive capacity by losing cell polarity and intercellular adhesions acquiring a mesenchymal and more motile phenotype, thus promoting cancer metastasis [11]. The molecular mechanisms driving EMT have been investigated and highlight the down-regulation of E-cadherin together with other epithelial specification genes paralleled by the up-regulation of mesenchymal markers such as N-cadherin, vimentin and fibronectin [11][12]. Expression of mesenchymal markers by primary tumors correlates with enhanced invasiveness and poorer clinical prognosis. Moreover, mounting evidence associates EMT to chemotherapy resistance [13][14][15][16]. In general, cancer cell lines with epithelial features are more sensitive to chemotherapy drugs compared to those displaying a mesenchymal phenotype; on the contrary, the acquisition of resistance to several drugs is accompanied by the expression of mesenchymal markers [17][18]. Many signals that unleash EMT are involved in triggering and maintaining the mesenchymal state and converge in the activation of a network of master transcriptional regulators (EMT-TF) that drive the EMT process. Among these, a major role is played by ZEB 1/2, Snail 1/2/3, and Twist 1/2 [12][19]. The same EMT-TF network is also active in PMT and there is evidence, both in vitro and in vivo, supporting a critical role for these factors in the acquisition of the MES phenotype [20][21][22]. As for EMT, PMT has been shown to have a role in conferring an unfavorable prognosis. Specifically, radiation and chemotherapy induced resistance by promoting a PN to MES phenotypic shift, therefore investigation of PMT mechanisms is critical for improving therapy selection and patient outcomes.

2. PMT in Multitherapy Resistance

Current treatments for GBM, consisting of radiotherapy and concomitant adjuvant chemotherapy with TMZ, are still ineffective, since the tumor inevitably relapses and the prognosis is extremely poor, being fatal in 90% of patients 5 years after initial diagnosis [2][23]. A sub-population of tumor cells with stem-like properties, the glioma stem cells (GSCs) or glioma-initiating cells (GICs), which are responsible for tumor initiation, is specifically endowed to resist or adapt to the standard therapies, leading to therapy resistance [23]. It has been recently proposed that GSCs can be sub-divided into two main groups, characterized by either a PN or a MES phenotype [24]. Segerman et al. have shown that a single GBM gives rise to many GIC clones with different resistance to therapies. However, they observed that, upon treatment with radiotherapy and different drugs, all clones become resistant to the same treatments acquiring a multitherapy resistance phenotype with different degrees of resistance along a continuous distribution, suggestive of a dynamic process in the GIC population [10]. The gene set enrichment analysis (GSEA) of these clones showed a clear connection of multitherapy resistance to MES signature on one side, and sensitivity to PN signature on the other side. Therefore, it is likely that a primary GBM contains both PN and MES GSCs, but the treatment pushes PMT in GSCs, resulting in a prevalence of MES GSCs in the recurrent tumor (Figure 1). The passage from PN to MES upon radio- and chemotherapy is governed by epigenetic changes, specifically DNA methylation, on regulatory elements of master regulators of the MES GBM subtype, such as FOSL2 [10][14]. It is likely that the inflammatory microenvironment consequent to the exposure to the therapeutic agents could be responsible for such dynamicity. More recently, Minata et al. reported that, upon exposure to IR, CD109 is highly induced, while CD133 is downregulated, in PN GSCs present at the invading edge of the tumor, which is often unresectable upon surgery. The resulting switch from PN to MES phenotype could explain the IR-dependent tumor recurrence. Mechanistically, IR activates NF-κB via ATM, which in turn induces CD109 via C/EBPβ. They also showed that CD109 acts upstream of the YAP/TAZ signaling pathway, which could contribute to the PMT of the CD109+ tumor cells [25]. However, due to the reversible nature of the process, elucidating the mechanisms of PMT may help to identify new strategies to sensitize GBM to treatment. Consistently, the blockage of STAT3 activation inhibits radiation-induced PMT, resulting in prolonged survival of mice with PN GBM [26]. Also, silencing of LncRNA-H19 decreases chemoresistance of human glioma cells to TMZ by suppressing PMT via the Wnt/β-catenin pathway [27].
Ijms 20 02746 g003 550
Figure 1. PMT upon radio- and chemotherapeutic treatment of GBM. A single GBM contains GSCs of both PN and MES phenotype. Upon treatment, most of them pass from the PN to the MES phenotype as a result of different treatment-dependent events, some of which are shown below. In purple: cells with proneural features; in grey: cells with mesenchymal features.
Another therapy experimented for GBM is the antiangiogenic therapy (e.g., bevacizumab/anti-VEGF) that, by reducing vascular permeability is thought to reduce the tumor burn of a highly vascularized cancer such as GBM. However, after an initial delay in tumor progression, chronic exposure to antiangiogenic therapy ultimately provoked an aggressive treatment-resistant phenotype [28]. Also, in this case, gene expression and GSEA of resistant clones showed an increase in genes associated with the MES GBM subtype, thus identifying a PMT in tumors resistant to antiangiogenic therapy [29].
Upregulation of MES markers with concomitant downregulation of the PN phenotype, consequent to increased intracellular levels of reactive oxygen species (ROS), was also observed in primary GSCs treated with the cannabinoid and redox modulator cannabidiol (CBD), thus suggesting a combinatorial approach consisting of CBD and small molecule inhibitors of ROS for a more successful treatment of GBM [23].

References

  1. Frank B. Furnari; Tim Fenton; Robert M. Bachoo; Akitake Mukasa; Jayne M. Stommel; Alexander Stegh; William C. Hahn; Keith L. Ligon; David N. Louis; Cameron Brennan; et al.Lynda ChinRonald A. DePinhoWebster K. Cavenee Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes & Development 2007, 21, 2683-2710, 10.1101/gad.1596707.
  2. Roger Stupp; Warren P. Mason; Martin Van Den Bent; Michael Weller; Barbara Fisher; Martin J.B. Taphoorn; Karl Belanger; Alba Brandes; Christine Marosi; Ulrich Bogdahn; et al.Jürgen CurschmannRobert C. JanzerSamuel K. LudwinThierry GorliaAnouk AllgeierDenis LacombeJ. Gregory CairncrossElizabeth EisenhauerRené Olivier Mirimanoff Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New England Journal of Medicine 2005, 352, 987-996, 10.1056/nejmoa043330.
  3. Antonio Omuro; Glioblastoma and Other Malignant Gliomas. JAMA 2013, 310, 1842-1850, 10.1001/jama.2013.280319.
  4. Maleeha Qazi; P. Vora; C. Venugopal; S. S. Sidhu; J. Moffat; C. Swanton; S. K. Singh; Intratumoral heterogeneity: pathways to treatment resistance and relapse in human glioblastoma. Annals of Oncology 2017, 28, 1448-1456, 10.1093/annonc/mdx169.
  5. Nicole Renee Parker; Peter Khong; Jonathon Fergus Parkinson; Viive Maarika Howell; Helen Ruth Wheeler; Molecular Heterogeneity in Glioblastoma: Potential Clinical Implications. Frontiers in Oncology 2015, 5, 55-55, 10.3389/fonc.2015.00055.
  6. Andrea Sottoriva; Inmaculada Spiteri; Sara G. M. Piccirillo; Anestis Touloumis; V. Peter Collins; John C. Marioni; Christina Curtis; Colin Watts; Simon Tavaré; Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proceedings of the National Academy of Sciences 2013, 110, 4009-4014, 10.1073/pnas.1219747110.
  7. Anoop P. Patel; Itay Tirosh; John J. Trombetta; Alex K. Shalek; Shawn M. Gillespie; Hiroaki Wakimoto; Daniel P. Cahill; Brian V. Nahed; William T. Curry; Robert L. Martuza; et al.David N. LouisOrit Rozenblatt-RosenMario L. SuvàAviv RegevBradley E. Bernstein Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 2014, 344, 1396-1401, 10.1126/science.1254257.
  8. Heidi S. Phillips; Samir Kharbanda; Ruihuan Chen; William F. Forrest; Robert H. Soriano; Thomas D. Wu; Anjan Misra; Janice M. Nigro; Howard Colman; Liliana Soroceanu; et al.P. Mickey WilliamsZora ModrusanBurt G. FeuersteinKen Aldape Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 2006, 9, 157-173, 10.1016/j.ccr.2006.02.019.
  9. Roel G.W. Verhaak; Katherine Hoadley; Elizabeth Purdom; Victoria Wang; Yuan Qi; Matthew D. Wilkerson; Christopher Miller; Li Ding; Todd Golub; Jill P. Mesirov; et al.Gabriele AlexeMichael LawrenceMichael O'KellyPablo TamayoBarbara A. WeirStacey GabrielWendy WincklerSupriya GuptaLakshmi JakkulaHeidi S. FeilerJ. Graeme HodgsonC. David JamesJann N. SarkariaCameron BrennanAri KahnPaul T. SpellmanRichard K. WilsonTerence P. SpeedJoe W. GrayMatthew MeyersonGad GetzCharles PerouD. Neil Hayes Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010, 17, 98-110, 10.1016/j.ccr.2009.12.020.
  10. Anna Segerman; Mia Niklasson; Caroline Haglund; Tobias Bergström; Malin Jarvius; Yuan Xie; Ann Westermark; Demet Sönmez; Annika Hermansson; Marianne Kastemar; et al.Zeinab Naimaie-AliFrida NybergMalin BerglundMagnus SundströmGöran HesselagerLene UhrbomMats GustafssonRolf LarssonMårten FryknäsBo SegermanBengt Westermark Clonal Variation in Drug and Radiation Response among Glioma-Initiating Cells Is Linked to Proneural-Mesenchymal Transition. Cell Reports 2016, 17, 2994-3009, 10.1016/j.celrep.2016.11.056.
  11. Raghu Kalluri; Robert A. Weinberg; The basics of epithelial-mesenchymal transition. Journal of Clinical Investigation 2009, 119, 1420-1428, 10.1172/jci39104.
  12. Ester Sánchez-Tilló; Yongqing Liu; Oriol de Barrios; Laura Siles; Lucia Fanlo; Miriam Cuatrecasas; Douglas Darling; Douglas C. Dean; Antoni Castells; Antonio Postigo; et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cellular and Molecular Life Sciences 2012, 69, 3429-3456, 10.1007/s00018-012-1122-2.
  13. Kari R. Fischer; Anna Durrans; Sharrell Lee; Jianting Sheng; Fuhai Li; Stephen T. C. Wong; Hyejin Choi; Tyler El Rayes; Seongho Ryu; Juliane S Troeger; et al.Robert F. SchwabeLinda T. VahdatNasser K. AltorkiVivek MittalDingcheng Gao Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015, 527, 472-476, 10.1038/nature15748.
  14. Xiaofeng Zheng; Julienne Carstens; Jiha Kim; Matthew Scheible; Judith Kaye; Hikaru Sugimoto; Chia-Chin Wu; Valerie S. LeBleu; Raghu Kalluri; Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature Cell Biology 2015, 527, 525-530, 10.1038/nature16064.
  15. Anurag Singh; J Settleman; EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010, 29, 4741-4751, 10.1038/onc.2010.215.
  16. Bethany N. Smith; Neil A. Bhowmick; Role of EMT in Metastasis and Therapy Resistance. Journal of Clinical Medicine 2016, 5, 17, 10.3390/jcm5020017.
  17. Samir E. Witta; Robert M. Gemmill; Fred R. Hirsch; Christopher D. Coldren; Karla Hedman; Larisa Ravdel; Barbara Helfrich; Rafal Dziadziuszko; Daniel C. Chan; Michio Sugita; et al.Zeng ChanAnna E BaronWilbur A FranklinHarry A. DrabkinLuc GirardAdi F. GazdarJohn D. MinnaPaul A. Bunn Restoring E-Cadherin Expression Increases Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cell Lines. Cancer Research 2006, 66, 944-950, 10.1158/0008-5472.can-05-1988.
  18. Bryan C. Fuchs; Tsutomu Fujii; Jon D. Dorfman; Jonathan M. Goodwin; Andrew X. Zhu; Michael Lanuti; Kenneth K. Tanabe; Epithelial-to-Mesenchymal Transition and Integrin-Linked Kinase Mediate Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Hepatoma Cells. Cancer Research 2008, 68, 2391-2399, 10.1158/0008-5472.can-07-2460.
  19. Steven Goossens; Niels Vandamme; Pieter Van Vlierberghe; Geert Berx; EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2017, 1868, 584-591, 10.1016/j.bbcan.2017.06.006.
  20. Svetlana A Mikheeva; Andrei M Mikheev; Audrey Petit; Richard Beyer; Robert G Oxford; Leila Khorasani; John-Patrick Maxwell; Carlotta A Glackin; Hiroaki Wakimoto; Inés González-Herrero; et al.Isidro Sánchez-GarcíaJohn R SilberPhilip J HornerRobert C Rostomily TWIST1 promotes invasion through mesenchymal change in human glioblastoma. Molecular Cancer 2010, 9, 194-194, 10.1186/1476-4598-9-194.
  21. K Savary; D Caglayan; L Caja; K Tzavlaki; S Bin Nayeem; T Bergström; Y Jiang; L Uhrbom; K Forsberg-Nilsson; B Westermark; et al.C-H HeldinM FerlettaA Moustakas Snail depletes the tumorigenic potential of glioblastoma. Oncogene 2013, 32, 5409-5420, 10.1038/onc.2013.67.
  22. Kin-Hoe Chow; Hee Jung Park; Joshy George; Keiko Yamamoto; Andrew D. Gallup; Joel H. Graber; Yuanxin Chen; Wen Jiang; Dennis A. Steindler; Eric G. Neilson; et al.Betty Y.S. KimKyuson Yun S100A4 Is a Biomarker and Regulator of Glioma Stem Cells That Is Critical for Mesenchymal Transition in Glioblastoma. Cancer Research 2017, 77, 5360-5373, 10.1158/0008-5472.can-17-1294.
  23. Eric Singer; Jonathon Judkins; Nathan Salomonis; Lisa Matlaf; Patricia Soteropoulos; Sean D McAllister; Liliana Soroceanu; Reactive oxygen species-mediated therapeutic response and resistance in glioblastoma. Cell Death & Disease 2015, 6, e1601-e1601, 10.1038/cddis.2014.566.
  24. G. Marziali; Michele Signore; Mariachiara Buccarelli; Sveva Grande; Alessandra Palma; Mauro Biffoni; Antonella Rosi; Quintino Giorgio D'Alessandris; Maurizio Martini; Luigi Maria Larocca; et al.Ruggero De MariaRoberto PalliniL. Ricci-Vitiani Metabolic/Proteomic Signature Defines Two Glioblastoma Subtypes With Different Clinical Outcome. Scientific Reports 2016, 6, 21557, 10.1038/srep21557.
  25. Mutsuko Minata; Alessandra Audia; Junfeng Shi; Songjian Lu; Joshua Bernstock; Marat S. Pavlyukov; Arvid Das; Sung-Hak Kim; Yong Jae Shin; Yeri Lee; et al.Harim KooKirti SnigdhaIndrayani WaghmareXing GuoAhmed MohyeldinDaniel Gallego-PerezJia WangDongquan ChenPeng ChengFarah MukheefMinerva ContrerasJoel F. ReyesBrian VaillantErik P. SulmanShi-Yuan ChengJames M. MarkertBakhos A. TannousXinghua LuMadhuri Kango-SinghL. James LeeDo-Hyun NamIchiro NakanoKrishna P. Bhat Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation. Cell Reports 2019, 26, 1893-1905.e7, 10.1016/j.celrep.2019.01.076.
  26. Jasmine Lau; Shirin Ilkhanizadeh; Susan Wang; Yekaterina A. Miroshnikova; Nicolas A. Salvatierra; Robyn A. Wong; Christin Schmidt; Valerie Marie Weaver; William A. Weiss; Anders I. Persson; et al. STAT3 Blockade Inhibits Radiation-Induced Malignant Progression in Glioma. Cancer Research 2015, 75, 4302-4311, 10.1158/0008-5472.can-14-3331.
  27. Linwei Jia; Yaohui Tian; Yonghan Chen; Gang Zhang; The silencing of LncRNA-H19 decreases chemoresistance of human glioma cells to temozolomide by suppressing epithelial-mesenchymal transition via the Wnt/β-Catenin pathway. OncoTargets and Therapy 2018, ume 11, 313-321, 10.2147/ott.s154339.
  28. Olivier Keunen; Mikael Johansson; Anaïs Oudin; Morgane Sanzey; Siti A. Abdul Rahim; Fred Fack; Frits Thorsen; Torfinn Taxt; Michal Bartoš; Radovan Jirik; et al.Hrvoje MileticJian WangDaniel StieberLinda StuhrIngrid MoenCecilie Brekke RyghRolf BjerkvigSimone Niclou Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proceedings of the National Academy of Sciences 2011, 108, 3749-3754, 10.1073/pnas.1014480108.
  29. Yuji Piao; Ji Liang; Lindsay Holmes; Verlene Henry; Erik Sulman; John F. De Groot; Acquired Resistance to Anti-VEGF Therapy in Glioblastoma Is Associated with a Mesenchymal Transition. Clinical Cancer Research 2013, 19, 4392-4403, 10.1158/1078-0432.ccr-12-1557.
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Monica Fedele
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Laura Cerchia
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Riccardo Sgarra
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