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.

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