FAK alternative splice mRNA variants expression pattern in colorectal cancer

Christel Devaud (1) , Anne-Françoise Tilkin-Mariamé (1) , Alix Vignolle-Vidoni (1) , Philippine Souleres (1) , Alexandre Denadai-Souza (1) , Corinne Rolland (1) , Christine Duthoit (2) , Catherine Blanpied (1) , Sophie Chabot (3) , Pascale Bouillé (2) , Philippe Lluel (3) , Nathalie Vergnolle (1) , Claire Racaud-Sultan (1) , Audrey Ferrand (1)

1 IRSD - Institut de Recherche en Santé Digestive
2 Vectalys SAS
3 Urosphère SAS

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 FAK 0 , FAK 28 and FAK 6) differentially expressed along the CRC process and the tumor sites. Our results highlight an association between FAK 0 and FAK 6 expressions and the metastatic potential of the most aggressive cell lines HT29 and HCT116, suggesting that FAK 0 and FAK 6 could represent aggressiveness markers in CRC. Our findings also suggest a more specific role for FAK 28 in the interactions between the tumors cells and their microenvironment. In conclusion, targeting FAK 0 , the common form of FAK, might not be a good strategy based on the numerous roles of this kinase in physiological processes. In contrast, FAK 6 or FAK 28 splice variants, or their corresponding protein isoforms, may putatively represent future therapeutic target candidates in the development of CRC primary tumors and metastasis.

Keywords: FAK; alternative splicing; colorectal cancer; metastases

Domains: Cancer; Genomics [q-bio.GN]

Christel Devaud, Anne-Françoise Tilkin-Mariamé, Alix Vignolle-Vidoni, Philippine Souleres, Alexandre Denadai-Souza, et al.. FAK alternative splice mRNA variants expression pattern in colorectal cancer. International Journal of Cancer, 2019, 145 (2), pp.494-502. ⟨10.1002/ijc.32120⟩. ⟨hal-02332277⟩