Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial-mesenchymal transition and colorectal cancer aggressiveness.
Adaptor Proteins, Signal Transducing
/ antagonists & inhibitors
Aged
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Colon
/ pathology
Colorectal Neoplasms
/ pathology
Datasets as Topic
Drug Resistance, Neoplasm
/ drug effects
Drug Screening Assays, Antitumor
Epithelial-Mesenchymal Transition
/ drug effects
Female
Focal Adhesion Kinase 1
/ metabolism
Focal Adhesions
/ pathology
Humans
Male
Neoplasm Invasiveness
/ pathology
Pancreatic Neoplasms
/ drug therapy
Proto-Oncogene Proteins c-crk
/ antagonists & inhibitors
RNA-Seq
Rectum
/ pathology
Signal Transduction
/ drug effects
Zinc Finger E-box-Binding Homeobox 1
/ metabolism
src-Family Kinases
/ metabolism
SASH1
colorectal cancer
focal adhesion
invasion
metastasis
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 09 2020
15 09 2020
Historique:
received:
20
08
2019
revised:
08
12
2019
accepted:
08
01
2020
pubmed:
10
3
2020
medline:
15
4
2021
entrez:
10
3
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Antineoplastic Agents
0
CRK protein, human
0
CRKL protein
0
Proto-Oncogene Proteins c-crk
0
ZEB1 protein, human
0
Zinc Finger E-box-Binding Homeobox 1
0
Focal Adhesion Kinase 1
EC 2.7.10.2
PTK2 protein, human
EC 2.7.10.2
src-Family Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1715-1731Informations de copyright
© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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