Abstract 2448: Modeling the mechanisms behind the biphasic expression of the PTK7 tyrosine kinase receptor in colorectal cancer
Authors: Laetitia Ganier, Anais Aulas, Olivier Cabaud, Alexia Lopresti, Kostyantyn Semenchenko, Pascal Finetti, Marine Gilabert, Anthony Goncalves, Claire Acquaviva, Daniel Birnbaum, Emilie Mamessier, Jean-Paul Borg
Journal: Cancer Research (2021)

Abstract Colorectal cancer (CRC) is the second deadliest cancer worldwide. Discovery of new biomarkers and therapeutic targets is thus essential (PMID: 27922044). CRC cells frequently reactivate developmental pathways such as WNT, Hedgehog and Hippo pathways, which participate to tumorigenesis and metastatic dissemination. The tyrosine kinase receptor PTK7 is a cell surface component from the WNT pathway involved in embryonic development in many species (PMID: 15229603). In retrospective studies, PTK7 was previously found overexpressed in CRC, an event associated with metastatic development, reduced metastases-free survival of non-metastatic patients, and resistance to chemotherapy (PMID: 25962058 and 21103379). PTK7 has pro-migratory and pro-metastatic functions in vitro and in vitro, but the mechanisms behind are not well understood yet. We recently conducted a prospective study collecting primary tumors, circulating tumor cells (CTCs) and metastases from CRC patients and evaluated expression of PTK7 in all types of samples at the mRNA and protein levels. PTK7 was confirmed as an independent poor prognosis marker in CRC with strong expression in primary tumors and metastases. Surprisingly, a large majority of CTCs were tested negative for the presence of PTK7 at their cell surface. We recapitulated this observation in a xenografted mouse model, as well as in an in vitro microfluidic setup preventing cell-matrix and cell-cell interactions of circulating CRC cells. Both results demonstrated the cell autonomous origin of PTK7 disappearance from CRC cells once in circulation. Interestingly, knockdown of PTK7 with small interfering RNA impaired the adhesion pattern of now PTK7-negative CRC cells on several matrix and promoted resistance to anoikis. A screen combining proximity labeling and mass spectrometry from CRC cells identified partners of PTK7 involved in cell adhesion, including integrins. In the absence of PTK7, two of them (ITGβ1 and ITGαV) had disabled function and expression, and their deregulation was associated with an increased phosphorylation of Focal Adhesion Kinase (FAK), a major actor of cancer cell survival and resistance to anoikis. We are currently investigating the mechanism of disappearance of PTK7 from the cell surface of CTCs and its consequence on drug resistance and metastatic dissemination of CRC cells. Citation Format: Laetitia Ganier, Anais Aulas, Olivier Cabaud, Alexia Lopresti, Kostyantyn Semenchenko, Pascal Finetti, Marine Gilabert, Anthony Goncalves, Claire Acquaviva, Daniel Birnbaum, Emilie Mamessier, Jean-Paul Borg. Modeling the mechanisms behind the biphasic expression of the PTK7 tyrosine kinase receptor in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2448.