ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/002/ERR3958882/ERR3958882_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/001/ERR3958871/ERR3958871_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/003/ERR3958883/ERR3958883_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/003/ERR3958873/ERR3958873_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/002/ERR3958872/ERR3958872_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/004/ERR3958884/ERR3958884_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/002/ERR3958882/ERR3958882_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/008/ERR3958878/ERR3958878_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/004/ERR3958884/ERR3958884_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/003/ERR3958883/ERR3958883_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/007/ERR3958877/ERR3958877_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/001/ERR3958881/ERR3958881_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/000/ERR3958880/ERR3958880_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/009/ERR3958879/ERR3958879_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/002/ERR3958872/ERR3958872_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/003/ERR3958873/ERR3958873_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/009/ERR3958879/ERR3958879_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/006/ERR3958876/ERR3958876_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/004/ERR3958874/ERR3958874_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/001/ERR3958881/ERR3958881_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/005/ERR3958875/ERR3958875_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/004/ERR3958874/ERR3958874_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/005/ERR3958875/ERR3958875_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/000/ERR3958880/ERR3958880_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/008/ERR3958878/ERR3958878_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/006/ERR3958876/ERR3958876_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/007/ERR3958877/ERR3958877_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR395/001/ERR3958871/ERR3958871_1.fastq.gzprimaryOK200GenomicsKlinikum rechts der Isar, II. Medizinische Klinikhttps://www.ebi.ac.uk/ena/browser/view/PRJEB36353Epithelial-mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly towards the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT regulator ZEB1 was significantly correlated in patient samples from colorectal cancer, especially in invasive regions. Further, high expression of CRK family genes was significantly associated with reduced survival in locally advanced colorectal cancer, as well as in pan-cancer datasets from the TCGA project. Thus, CRK family adaptor proteins are promising therapeutic targets to counteract EMT, chemoresistance, metastasis formation and minimal residual disease. As proof of concept, CRK family-mediated oncogenic signaling was successfully inhibited by a peptide-based inhibitor.ENADsrc, src-1, Colorectal Neoplasm, Epithelial Mesenchymal Transformation, Colorectal Cancer, CRKII, Dsrc41, Neoplasms, D-src, pp60v-src, fak, Epithelial Mesenchymal Transition, CT28129, Crko, CG14471, C-src1, Gene, Su(Raf)1, Dm SRC1, Tumor, autosomal dominant, Crk-II, Dm SRC41, DSrc, CrkIII, Colorectal, colorectal cancer, Fak56D, DmHD-358, Roles, src64, dsrc, Gene Products, Concepts, DFak, DFAK, mKIAA4203, Dcrk, p60-Src, Dfak56, Dmel_CG7873, CG10023, Colorectal Tumors, Src64, Kiaa4203, Src42a, Dsrc64, src64B, CG7524, xsrc, Colorectal Carcinomas, CDPK-related kinase, DmFAK, Colorectal Tumor, epithelial-mesenchymal transition, Crk-III, large intestine cancer, D-Crk, D-CRK, cancer of the large intestine, FAK1, ASV, DmelCG1587, ARPC5, Dfak, Role Concepts, DSrc64, mesenchymal cell differentiation from epithelial cell, dtk-5, SRC 42A, HD-358, pp60c-src, colorectal (colon or rectal) cancer., Transition, SRC42A, DSrc64B, fak56, somatic mutation, focal adhesion kinase activity, single organism signaling, Tk5, DSRC64, Tumors, Cancer, Transformation, Fadk, Carcinoma, Src42, Src41, pp125FAK, CG44128, src42a, csrc, Proteins, DmHD-29, dtk5, CROOKED, Epithelial-Mesenchymal, Fak56, Crk-I, p125FAK, Concept, Su(phl)1, DmelCG44128, FADK, Role Concept, FRNK, EMT, Protein, HD-29, src42A, Role, Neoplasm, src64b, T15B16_22, SK2-4, CRC, CG7873, Colorectal Cancers, Epithelial-Mesenchymal Transformation, Dsrc42A, SRC 64B, Su(D-raf)1, T15B16.22, CRK, DSrc42A, Carcinomas, large bowel cancer, l(2)k10108, Src, DmelCG10023, Src1, SRC1, dSrc, susceptibility to, Colorectal Carcinoma, MRE5, c-SRC, CG1587, p38, AW259666, Dmel_CG14471, Crk3, Cancers, c-Crk, DFak56, cancer of large bowel, crk, PPP1R71, Protein Gene Products, DmelCG7524, Gene Proteins, src, colon cancer, DCrk, signalling process, src42, Su1, FAK, cancer of the large bowel, c-src, dCRK, dCrk, cancer of large intestine, D-Src64B, src1, Dtk5, src2, Dsrc64BDsrc, Tcsk, src-1, CRKII, Organic cation transporter 3, Dsrc41, D-src, pp60v-src, fak, CT28129, Crko, CG14471, C-src1, Gene, Su(Raf)1, Dm SRC1, OCT3, Crk-II, Dm SRC41, DSrc, CrkIII, Fak56D, DmHD-358, src64, dsrc, Gene Products, DFak, DFAK, mKIAA4203, Dcrk, p60-Src, Dfak56, Dmel_CG7873, CG10023, EMTH, Src64, Kiaa4203, Src42a, Dsrc64, src64B, CG7524, xsrc, LPFS1, CDPK-related kinase, DmFAK, epithelial-mesenchymal transition, Crk-III, D-Crk, D-CRK, FAK1, ASV, DmelCG1587, ARPC5, Dfak, DSrc64, mesenchymal cell differentiation from epithelial cell, dtk-5, SRC 42A, HD-358, pp60c-src, SRC42A, DSrc64B, fak56, focal adhesion kinase activity, single organism signaling, Tk5, DSRC64, Fadk, Src42, Src41, pp125FAK, CG44128, src42a, csrc, Proteins, DmHD-29, dtk5, CROOKED, Fak56, Crk-I, p125FAK, Su(phl)1, DmelCG44128, FADK, FRNK, EMT, Tsk, Emt, Protein, HD-29, src42A, src64b, LYK., T15B16_22, SK2-4, CG7873, Dsrc42A, SRC 64B, Su(D-raf)1, T15B16.22, CRK, DSrc42A, l(2)k10108, Src, DmelCG10023, Src1, SRC1, dSrc, PSCTK2, MRE5, c-SRC, CG1587, p38, AW259666, Dmel_CG14471, Crk3, c-Crk, DFak56, crk, PPP1R71, Protein Gene Products, DmelCG7524, Gene Proteins, src, DCrk, signalling process, src42, Su1, FAK, c-src, Extraneuronal monoamine transporter, dCRK, dCrk, D-Src64B, src1, Dtk5, src2, Dsrc64BfalseCRK proteins are essential for SRC/FAK signaling in EMTNovel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial-mesenchymal transition and colorectal cancer aggressiveness2020-01-242020-03-03PRJEB36353