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Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial–mesenchymal transition and colorectal cancer aggressiveness
Author(s) -
Franke Fabian C.,
Slusarenko Benjamin O.,
Engleitner Thomas,
Johannes Widya,
Laschinger Melanie,
Rad Roland,
Nitsche Ulrich,
Janssen KlausPeter
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32955
Subject(s) - adapter molecule crk , signal transducing adaptor protein , cancer research , epithelial–mesenchymal transition , biology , metastasis , rap1 , cancer , signal transduction , proto oncogene tyrosine protein kinase src , focal adhesion , microbiology and biotechnology , genetics
Epithelial–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 toward 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 samples from colorectal cancer patients, 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.