Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1

Coralie Reger De Moura; Baptiste Louveau; Fanélie Jouenne; Paul Vilquin; Maxime Battistella; Yaelle Bellahsen-Harrar; Aurélie Sadoux; Suzanne Menashi; Nicolas Dumaz; Céleste Lebbé; Samia Mourah

doi:10.1038/s41388-024-03014-3

Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1

Oncogene. 2024 Apr 3. doi: 10.1038/s41388-024-03014-3. Online ahead of print.

Authors

Coralie Reger De Moura^#^{1

2}, Baptiste Louveau^#^{1

2}, Fanélie Jouenne^{1

2}, Paul Vilquin¹, Maxime Battistella³, Yaelle Bellahsen-Harrar³, Aurélie Sadoux¹, Suzanne Menashi^{1

2}, Nicolas Dumaz², Céleste Lebbé^{2

4}, Samia Mourah^{5

6}

Affiliations

¹ Department of Pharmacology and Tumor Genomics, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France.
² Université Paris Cité, INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010, Paris, France.
³ Department of Pathology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France.
⁴ Department of Dermatology and CIC, Hôpital Saint Louis, Cancer Institute, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France.
⁵ Department of Pharmacology and Tumor Genomics, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France. samia.mourah@aphp.fr.
⁶ Université Paris Cité, INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010, Paris, France. samia.mourah@aphp.fr.

^# Contributed equally.

PMID: 38570692
DOI: 10.1038/s41388-024-03014-3

Abstract

The role of the focal adhesion protein kindlin-3 as a tumor suppressor and its interaction mechanisms with extracellular matrix constitute a major field of investigation to better decipher tumor progression. Besides the well-described role of kindlin-3 in integrin activation, evidence regarding modulatory functions between melanoma cells and tumor microenvironment are lacking and data are needed to understand mechanisms driven by kindlin-3 inactivation. Here, we show that kindlin-3 inactivation through knockdown or somatic mutations increases BRAF^V600mut melanoma cells oncogenic properties via collagen-related signaling by decreasing cell adhesion and enhancing proliferation and migration in vitro, and by promoting tumor growth in mice. Mechanistic analysis reveals that kindlin-3 interacts with the collagen-activated tyrosine kinase receptor DDR1 (Discoidin domain receptor 1) modulating its expression and its interaction with β1-integrin. Kindlin-3 knockdown or mutational inactivation disrupt DDR1/β1-integrin complex in vitro and in vivo and its loss improves the anti-proliferative effect of DDR1 inhibition. In agreement, kindlin-3 downregulation is associated with DDR1 over-expression in situ and linked to worse melanoma prognosis. Our study reveals a unique mechanism of action of kindlin-3 in the regulation of tumorigenesis mediated by the collagen-activated tyrosine kinase receptor DDR1 thus paving the way for innovative therapeutic targeting approaches in melanoma.