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• W3048888411 abstract "The extracellular matrix (ECM) plays a major role in cancer progression through its increased deposition and alignment. In this issue of Developmental Cell, Fattet et al. reveal a pathway in which ECM stiffness promotes EPHA2/LYN complex activation, leading to TWIST1 nuclear localization and triggering EMT in breast cancer. The extracellular matrix (ECM) plays a major role in cancer progression through its increased deposition and alignment. In this issue of Developmental Cell, Fattet et al. reveal a pathway in which ECM stiffness promotes EPHA2/LYN complex activation, leading to TWIST1 nuclear localization and triggering EMT in breast cancer. The ECM has been described as a key player during tumorigenesis and metastasis formation. Indeed, alterations in ECM composition, organization, and biomechanical signaling occur all along the metastatic journey. In breast cancer, increased ECM stiffness and a more aligned matrix are often observed, promoting cancer cell migration and invasion, notably through epithelial-mesenchymal transition (EMT). ECM remodeling and EMT are associated with metastasis process and a poor prognosis (Kai et al., 2019Kai F. Drain A.P. Weaver V.M. The extracellular matrix modulates the metastatic journey.Dev. Cell. 2019; 49: 332-346Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). In this issue of Developmental Cell, Fattet et al., 2020Fattet L. Jung H.-Y. Matsumoto M.W. Aubol B.E. Kumar A. Adams J.A. Chen A.C. Sah R.L. Engler A.J. Pasquale E.B. et al.Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex.Dev. Cell. 2020; 54 (this issue): 302-316Abstract Full Text Full Text PDF Scopus (18) Google Scholar reveal a signaling pathway that is activated in response to collagen alignment and associated rigidity, and that is involved in metastasis formation. This ECM stiffness-induced mechanotransduction promotes breast cancer cell EMT and invasion through EPHA2 phosphorylation, LYN activation, and TWIST phosphorylation, mediating its nuclear localization. EPHA2 and LYN are known to be involved in cancer invasion. EPHA2 is a tyrosine kinase receptor, and its expression (at the mRNA and protein levels) is associated with poor prognosis and cell invasion in a large number of cancers (Ieguchi and Maru, 2019Ieguchi K. Maru Y. Roles of EphA1/A2 and ephrin-A1 in cancer.Cancer Sci. 2019; 110: 841-848Crossref PubMed Scopus (26) Google Scholar). Additionally, the EPHA2 receptor is a major player in resistance to treatment in ovarian cancer (Moyano-Galceran et al., 2020Moyano-Galceran L. Pietilä E.A. Turunen S.P. Corvigno S. Hjerpe E. Bulanova D. Joneborg U. Alkasalias T. Miki Y. Yashiro M. et al.Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.EMBO Mol. Med. 2020; 12: e11177Crossref PubMed Scopus (13) Google Scholar). Specifically, ERK and RSK signaling induces cooperation between the EPHA2 and GPRC5A receptors, which promotes ovarian cancer resistance to chemotherapies. LYN is a tyrosine kinase that promotes proliferation and tumor cell growth in various cancers, such as leukemia, lymphoma, and several solid cancers. LYN expression is furthermore associated with colorectal cancer metastatic stages. In colorectal cancer, CD44 activates LYN, which thereby induces AKT signaling, promoting drug resistance. LYN also promotes EMT in basal-like breast cancer, but its role remains poorly understood (Ingley, 2012Ingley E. Functions of the Lyn tyrosine kinase in health and disease.Cell Commun. Signal. 2012; 10: 21Crossref PubMed Scopus (90) Google Scholar). However, EPHA2 and LYN were not previously known to interact. In their study, Fattet et al., 2020Fattet L. Jung H.-Y. Matsumoto M.W. Aubol B.E. Kumar A. Adams J.A. Chen A.C. Sah R.L. Engler A.J. Pasquale E.B. et al.Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex.Dev. Cell. 2020; 54 (this issue): 302-316Abstract Full Text Full Text PDF Scopus (18) Google Scholar use an elegant technique to test ECM rigidity in a 3D system in order to mimic breast tumor tissue. They show that collagen I alignment and associated stiffness induce LYN activation, leading to the phosphorylation of TWIST1 and promoting its nuclear localization. The activation of Twist then promotes EMT and invasion. To provide further insight into the molecular mechanism driving LYN activation, the authors performed immunoprecipitation experiments followed by mass spectrometry analysis to identify LYN-interacting proteins. After validating the top candidate using shRNA knockdown experiments, they showed that LYN activation was mediated by EPHA2. They further demonstrated that ECM stiffness promotes ERK/RSK2 activation, leading to ligand-independent EPHA2 S897 phosphorylation. This phosphorylation is necessary for stiffness-induced LYN/TWIST1 mechanotransduction, leading to EMT and invasion. All of these results were confirmed in vivo, showing that inhibition of either EPHA2, LYN, or RSK decreased tumor progression, invasion, and metastasis. Finally, the authors validated their results in human breast tumor samples using second harmonic generation (SHG) microscopy imaging, showing that aligned and stiff ECM fibers correlate with EPHA2 phosphorylation and tumor aggressiveness. Together, these findings define an EPHA2- and LYN-dependent mechanosensitive pathway that promotes tumor invasion. However, little is known about the exact mechanism that leads to EPHA2 activation. Fattet et al., 2020Fattet L. Jung H.-Y. Matsumoto M.W. Aubol B.E. Kumar A. Adams J.A. Chen A.C. Sah R.L. Engler A.J. Pasquale E.B. et al.Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex.Dev. Cell. 2020; 54 (this issue): 302-316Abstract Full Text Full Text PDF Scopus (18) Google Scholar propose that different sensors could cooperate to induce this mechanostransduction. Indeed, we hypothesize that EPHA2 may be activated by two non-exclusive mechanisms: cooperation with an ECM co-receptor and/or mechanical signals (Figure 1). EPHA2 receptor could cooperate with different collagen I receptors, such as integrin or CD44. For instance, EPHA2 cooperation with CD44 promotes migration and invasion in colorectal cancer. On the other hand, in this study, Fattet et al., 2020Fattet L. Jung H.-Y. Matsumoto M.W. Aubol B.E. Kumar A. Adams J.A. Chen A.C. Sah R.L. Engler A.J. Pasquale E.B. et al.Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex.Dev. Cell. 2020; 54 (this issue): 302-316Abstract Full Text Full Text PDF Scopus (18) Google Scholar showed that ERK and RSK induce EPHA2 activation, promoting LYN induction. Different studies demonstrated that DDR2, another collagen receptor, could activate ERK, and one study even demonstrated LYN as a DDR2 target (Iwai et al., 2013Iwai L.K. Payne L.S. Luczynski M.T. Chang F. Xu H. Clinton R.W. Paul A. Esposito E.A. Gridley S. Leitinger B. et al.Phosphoproteomics of collagen receptor networks reveals SHP-2 phosphorylation downstream of wild-type DDR2 and its lung cancer mutants.Biochem. J. 2013; 454: 501-513Crossref PubMed Scopus (56) Google Scholar). Consequently, DDR2 is a potential EPHA2 co-receptor and could participate in LYN activation. We hypothesize that the interaction of stiff and aligned collagen I with the EPHA2 ECM co-receptor (e.g., CD44 or DDRs) will lead to its own activation. This would induce ERK/RSK, which could activate EPHA2/LYN and promote TWIST1phosphorylation and nuclear localization. On the stiff ECM used in this study, the authors could test this hypothesis using EPHA2 immunoprecipitation followed by mass spectrometry analysis, or testing EPHA2 phosphorylation by a phospho-tyrosine kinase assay. Fattet et al., 2020Fattet L. Jung H.-Y. Matsumoto M.W. Aubol B.E. Kumar A. Adams J.A. Chen A.C. Sah R.L. Engler A.J. Pasquale E.B. et al.Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex.Dev. Cell. 2020; 54 (this issue): 302-316Abstract Full Text Full Text PDF Scopus (18) Google Scholar also show that cancer cells on a stiff matrix secrete fibronectin. Different studies have demonstrated that EPHA2 increases fibronectin expression in breast cancer cells, promoting tumor cell growth and survival (Hu et al., 2004Hu M. Carles-Kinch K.L. Zelinski D.P. Kinch M.S. EphA2 induction of fibronectin creates a permissive microenvironment for malignant cells.Mol. Cancer Res. 2004; 2: 533-540PubMed Google Scholar). It is therefore possible that a feedback loop exists, in which EPHA2 promotes fibronectin secretion, and then the binding of fibronectin to another co-receptor (such as integrin α5β1 or CD44) induces EPHA2 activation. In summary, EPHA2 activation may be mediated by a co-receptor in two ways: via direct binding of collagen I to a co-receptor, or via a feedback loop with fibronectin secretion by cancer cells. An alternative or complementary way to induce EPHA2 activation would be mechanical, without any ligand binding. Cells can sense, respond to, and be regulated by mechanotransduction (Ayad et al., 2019Ayad N.M.E. Kaushik S. Weaver V.M. Tissue mechanics, an important regulator of development and disease.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2019; 374: 20180215Crossref PubMed Scopus (17) Google Scholar). In a previous study, the same team showed that a stiff ECM increases β1 integrin clustering, promoting PI3K/AKT and ERK signaling as well as EMT through TWIST1 nuclear translocation in breast cancer (Wei et al., 2015Wei S.C. Fattet L. Tsai J.H. Guo Y. Pai V.H. Majeski H.E. Chen A.C. Sah R.L. Taylor S.S. Engler A.J. Yang J. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway.Nat. Cell Biol. 2015; 17: 678-688Crossref PubMed Scopus (411) Google Scholar). However, in the present work, the authors demonstrate that ECM alignment induces ERK/RSK activation, leading to EPHA2 activation, independently of integrin contribution. Another possibility is that ECM stiffness modifies membrane forces and tension to activate membrane proteins. As observed in physiological development and some cancers, ECM stiffness induces nuclear translocation of transcription factors to regulate cellular functions, such as EMT or proliferation (Wei et al., 2015Wei S.C. Fattet L. Tsai J.H. Guo Y. Pai V.H. Majeski H.E. Chen A.C. Sah R.L. Taylor S.S. Engler A.J. Yang J. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway.Nat. Cell Biol. 2015; 17: 678-688Crossref PubMed Scopus (411) Google Scholar). In tumors, notably during collective cancer cell migration, cells that are not in direct contact with the ECM can still sense the tension of other cell membranes through cadherins and DDRs at cell-cell junctions. Subsequently, through different pathways like MAL/SRF and YAP/TAZ (Foster et al., 2017Foster C.T. Gualdrini F. Treisman R. Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics.Genes Dev. 2017; 31: 2361-2375Crossref PubMed Scopus (75) Google Scholar), cells propagate these forces to the actin cytoskeleton, changing their cell contractility and inducing signaling cascades such as EMT. Moreover, cytoskeleton modifications, such as filamentous actin assembly and recycling, are necessary for cell migration. For example, during differentiation of neural stem cells, ECM stiffness can increase RhoA and Cdc42 expressions, inducing contractility and cell stiffness (Ayad et al., 2019Ayad N.M.E. Kaushik S. Weaver V.M. Tissue mechanics, an important regulator of development and disease.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2019; 374: 20180215Crossref PubMed Scopus (17) Google Scholar). Similarly, we can postulate that, during cancer, ECM stiffness could modify plasma membrane tension to upregulate pathways involved in tumor cell migration. The study by Fattet et al., 2020Fattet L. Jung H.-Y. Matsumoto M.W. Aubol B.E. Kumar A. Adams J.A. Chen A.C. Sah R.L. Engler A.J. Pasquale E.B. et al.Matrix rigidity controls epithelial-mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex.Dev. Cell. 2020; 54 (this issue): 302-316Abstract Full Text Full Text PDF Scopus (18) Google Scholar highlights a pathway induced by ECM stiffness in breast cancer. The next step will be to decipher the EPHA2 activation mechanism, whether it involves an ECM co-receptor or mechanical activation, and to determine if this mechanism is applicable to other cancers. Matrix Rigidity Controls Epithelial-Mesenchymal Plasticity and Tumor Metastasis via a Mechanoresponsive EPHA2/LYN ComplexFattet et al.Developmental CellJune 22, 2020In BriefFattet et al. identified a EPHA2/LYN/TWIST1 signaling cascade activated by mechanical forces from the extracellular matrix to promote epithelial-mesenchymal transition and cell invasion. They demonstrate that activation of this mechanotransduction pathway promotes breast tumor invasion and metastasis and is involved in human breast cancer metastasis. Full-Text PDF Open Archive" @default.
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• W3048888411 title "Linking Matrix Rigidity with EMT and Cancer Invasion" @default.
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