Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. During EMT, tumor cells undergo tight junction dissolution, disruption of apical–basal polarity, and reorganization of the cytoskeletal architecture, which enable cells to develop an invasive phenotype. In cancer cells, EMT is abnormally regulated by extracellular stimuli derived from the tumor microenvironment, including growth factors and inflammatory cytokines, along with intra-tumoral physical stresses such as hypoxia. Therefore, EMT programming allows tumor cells to adapt to the constant changes of the human tumor microenvironment, and thus to successfully metastasize. This pathway summarizes the major signaling pathways and inducers that promote EMT in CRC.
A set of core transcription factors regulate EMT: SNAIL family of zinc-finger transcription factors SNAIL/SLUG; the zinc finger E-box binding homeobox (ZEB) family of transcription factors ZEB1/ZEB2, and the TWIST family of basic helix-loop-helix (bHLH) transcription factors TWIST1/TWIST2.
(Adapted from Vu et al.) Phosphorylation sites were added based on information from PhosphoSitePlus (R), www.phosphosite.org.
Proteins on this pathway have targeted assays available via the [https://assays.cancer.gov/available_assays?wp_id=WP4239 CPTAC Assay Portal]a43ea0d47bccadeab9d1ed92parentid=P49841; parentsymbol=GSK3B; site=SGRPRttsFAEsCkP; position=ser9; sitegrpid=449111; ptm=p; direction=dparentid=Q15672; parentsymbol=TWIST1; site=GGGDEPGsPAQGkRG; position=ser68; sitegrpid=18905000; ptm=p; direction=uparentid=O95863; parentsymbol=SNAI1; site=TsLsDEDsGkGsQPP; position=ser96; sitegrpid=455883; ptm=p; direction=dparentid=O95863; parentsymbol=SNAI1; site=TsLsDEDsGkGsQPP; position=ser96; sitegrpid=455883; ptm=p; direction=dparentid=O95863; parentsymbol=SNAI1; site=TsLsDEDsGkGsQPP; position=ser96; sitegrpid=455883; ptm=p; direction=dparentid=O95863; parentsymbol=SNAI1; site=QACARTFsRMsLLHK; position=ser246; sitegrpid=455616; ptm=p; direction=dparentid=O95863; parentsymbol=SNAI1; site=QGHVRtHtGEkPFSC; position=thr203; sitegrpid=21400402; ptm=p; direction=dparentid=Q15672; parentsymbol=TWIST1; site=GGGDEPGsPAQGkRG; position=ser68; sitegrpid=18905000; ptm=p; direction=uparentid=O95863; parentsymbol=SNAI1; site=SFLVRKPsDPNRKPN; position=ser11; sitegrpid=11493500; ptm=p; direction=dbd2d46d46d46a90d46ac2a6fc20d46d46a43d46a0cd46d46d46afeafed46d46d46d4624556840PubMedMolecular mechanisms of epithelial-mesenchymal transition.Nat Rev Mol Cell Biol2014Lamouille SXu JDerynck R14715079PubMedMolecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells.Biochem J2004De Bosscher KHill CSNicolás FJcancer pathwayPW:0000605Pathway Ontology12821112PubMedRole of Smad4 (DPC4) inactivation in human cancer.Biochem Biophys Res Commun2003Miyaki MKuroki T26269761PubMedOverexpression of forkhead Box C2 promotes tumor metastasis and indicates poor prognosis in colon cancer via regulating epithelial-mesenchymal transition.Am J Cancer Res2015Li QWu JWei PXu YZhuo CWang YLi DCai S10479724PubMedInactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.Mutat Res1999Koyama MIto MNagai HEmi MMoriyama Y19679400PubMedFrequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer.Pathol Res Pract2009Neumann JZeindl-Eberhart EKirchner TJung Adisease of cellular proliferationDOID:14566Disease23856032PubMedFOXM1 promotes the epithelial to mesenchymal transition by stimulating the transcription of Slug in human breast cancer.Cancer Lett2013Yang CChen HTan GGao WCheng LJiang XYu LTan Y29258163PubMedRegulation of EMT in Colorectal Cancer: A Culprit in Metastasis.Cancers (Basel)2017Vu TDatta PKcolorectal cancerDOID:9256Disease23723077PubMedUnraveling the role of FOXQ1 in colorectal cancer metastasis.Mol Cancer Res2013Abba MPatil NRasheed KNelson LDMudduluru GLeupold JHAllgayer H18316791PubMedWild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.J Clin Oncol2008Amado RGWolf MPeeters MVan Cutsem ESiena SFreeman DJJuan TSikorski RSuggs SRadinsky RPatterson SDChang DD8898652PubMedSomatic alterations of the DPC4 gene in human colorectal cancers in vivo.Gastroenterology1996Takagi YKohmura HFutamura MKida HTanemura HShimokawa KSaji S32746883PubMedPDCD6 cooperates with C-Raf to facilitate colorectal cancer progression via Raf/MEK/ERK activation.J Exp Clin Cancer Res2020Wang XWu FWang HDuan XHuang RTuersuntuoheti ASu LYan SZhao YLu YLi KYao JLuo ZGuo LLiu JChen XHu HLi XBao MBi XDu BMiao SCai JWang LZhou HYing JSong WZhao H23045246PubMedProspero homeobox 1 promotes epithelial-mesenchymal transition in colon cancer cells by inhibiting E-cadherin via miR-9.Clin Cancer Res2012Lu MHHuang CCPan MRChen HHHung WCcolon epithelial cellCL:0011108Cell Type21285253PubMedForkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis.Cancer Res2011Zhang HMeng FLiu GZhang BZhu JWu FEthier SPMiller FWu G25514926PubMedPhosphoSitePlus, 2014: mutations, PTMs and recalibrations.Nucleic Acids Res2015Hornbeck PVZhang BMurray BKornhauser JMLatham VSkrzypek E25656897PubMedPrometastatic NOTCH Signaling in Colon Cancer.Cancer Discov2015Kranenburg O