FAK alternative splice mRNA variants expression pattern in colorectal cancer

Abstract

The Focal adhesion kinase (FAK) is a ubiquitous cytoplasmic tyrosine‐kinase promoting tumor progression and metastasis processes by acting in cancer cells and their tumor microenvironment partners. FAK overexpression in primary colon tumors and their metastasis is associated to poor colorectal cancer (CRC) patients’ outcome. Eight FAK mRNA alternative splice variants have been described and contribute to additional level of FAK activity regulation, some of them corresponding to overactivated FAK isoforms. To date, FAK mRNA alternative splice variants expression and implication in CRC processes remain unknown. Here, using different human CRC cells lines displaying differential invasive capacities in an in vivo murine model recapitulating the different steps of CRC development from primary tumors to liver and lung metastasis, we identified three out of the eight mRNA variants (namely FAK0, FAK28 and FAK6) differentially expressed along the CRC process and the tumor sites. Our results highlight an association between FAK0 and FAK6 expressions and the metastatic potential of the most aggressive cell lines HT29 and HCT116, suggesting that FAK0 and FAK6 could represent aggressiveness markers in CRC. Our findings also suggest a more specific role for FAK28 in the interactions between the tumors cells and their microenvironment. In conclusion, targeting FAK0, the common form of FAK, might not be a good strategy based on the numerous roles of this kinase in physiological processes. In contrast, FAK6 or FAK28 splice variants, or their corresponding protein isoforms, may putatively represent future therapeutic target candidates in the development of CRC primary tumors and metastasis.

Colon-specific immune microenvironment regulates cancer progression versus rejection

“…Orthotopic xenograft models of CRC established in highly immunocompromised mice recapitulate many features of human pathology and have helped to elucidate several molecular mechanisms involved in CRC progression. [12][13][14] Nonetheless, human CRC cells xenografted in immunodeficient mice are not exposed to an immune response, which limits their relevance in terms of clinical translation. 15 Therefore, in vivo syngeneic orthotopic models are needed to understand the impact of the local immune response during CRC development.…”

Identification of an alternative splicing signature as an independent factor in colon cancer

“…Devaud et al [ 30 ] revealed that several AS variants of FAK might be used as potential biomarkers and treatment targets in the development and metastasis of colorectal cancer. Flodrops et al [ 31 ] found that TIMP1 intron 3 retention could affect the progression of colon cancer.…”

Colon-specific immune microenvironment regulates cancer progression versus rejection

“…Mice were implanted intra-colon (IC), into the caecum, as previously described [11] [12]. 1x10 6 or 3x10 6 viable tumor cells were injected IC sub-serosa.…”

“…Orthotopic xenograft models of CRC established in highly immunocompromised mice recapitulate many features of human pathology and have helped to elucidate several molecular mechanisms involved in CRC progression [11][12][13]. Nonetheless, human CRC cells xenografted in immunodeficient mice are not exposed to an immune response, which limits their relevance in terms of clinical translation [14].…”