Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells

Maëva Chauvin (1) , Véronique Garambois (1) , Pierre-Emmanuel Colombo (1) , Myriam Chentouf (1) , Laurent Gros (1) , Jean-Paul Brouillet (2) , Bruno Robert (1) , Marta Jarlier (3) , Karen Dumas , Pierre Martineau (1) , Isabelle Navarro-Teulon (1) , David Pépin (4) , Thierry Chardès (1) , André Pèlegrin (1)

1 IRCM - U1194 Inserm - UM - Institut de Recherche en Cancérologie de Montpellier
2 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
3 ICM - Institut régional de Cancérologie de Montpellier
4 HMS - Harvard Medical School [Boston]

In ovarian carcinoma, anti-Müllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets. Here, AMH dose-dependent effect on signaling and proliferation was analyzed in four ovarian cancer cell lines, including sex cord stromal/granulosa cell tumors and high grade serous adenocarcinomas (COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN). As previously shown, incubation with exogenous AMH at concentrations above the physiological range (12.5–25 nM) decreased cell viability. Conversely, physiological concentrations of endogenous AMH improved cancer cell viability. Partial AMH depletion by siRNAs was sufficient to reduce cell viability in all four cell lines, by 20% (OVCAR8 cells) to 40% (COV434-AMHRII cells). In the presence of AMH concentrations within the physiological range (5 to 15 pM), the newly developed anti-AMH B10 antibody decreased by 25% (OVCAR8) to 50% (KGN) cell viability at concentrations ranging between 3 and 333 nM. At 70 nM, B10 reduced clonogenic survival by 57.5%, 57.1%, 64.7% and 37.5% in COV434-AMHRII, SKOV3-AMHRII, OVCAR8 and KGN cells, respectively. In the four cell lines, B10 reduced AKT phosphorylation, and increased PARP and caspase 3 cleavage. These results were confirmed in ovarian cancer cells isolated from patients’ ascites, demonstrating the translational potential of these results. Furthermore, B10 reduced COV434-MISRII tumor growth in vivo and significantly enhanced the median survival time compared with vehicle (69 vs 60 days; p = 0.0173). Our data provide evidence for a novel pro-survival autocrine role of AMH in the context of ovarian cancer, which was targeted therapeutically using an anti-AMH antibody to successfully repress tumor growth.

Domaines: Cancer; Gynécologie et obstétrique; Endocrinologie et métabolisme

Maëva Chauvin, Véronique Garambois, Pierre-Emmanuel Colombo, Myriam Chentouf, Laurent Gros, et al.. Anti-Müllerian hormone (AMH) autocrine signaling promotes survival and proliferation of ovarian cancer cells. Scientific Reports, 2021, 11, pp.2231. ⟨10.1038/s41598-021-81819-y⟩. ⟨hal-03131997⟩