Cancer-associated mesothelial cells are regulated by the anti-Müllerian hormone axis

We’re excited to finally share our newest study by Maeva Chauvin et al. in CellReports on the role of the AMH-AMHR2 paracrine axis in ovarian cancer, overturning 40 years of research in the field and Identifying a potential new immunotherapy target for ovarian cancer: cancer-associated mesothelial cells.

One the reasons that treating this disease has been so challenging is that tumors often become resistant to chemotherapies, and generally respond poorly to immunotherapies. While much of the research on overcoming resistance and efforts to develop new therapies have focused on the cancer cells, it has often ignored the many other cell types of the tumor. Indeed, cancer cells have the ability to reprogram the cells around them to nurture the tumor and help evade the patient’s immune system. One of these cells is the mesothelial cell, which represents the point of first contact of ovarian cancer cells during peritoneal metastasis.  In this study, we show how cancer cell reprogram these mesothelial cells into cancer-associated-mesothelial cell, which then promote the growth of the tumor. Importantly we identify one of the signals, a hormone called Anti-Müllerian hormone, which is used by cancer cells reprogram and control mesothelial cells. We show that disrupting this signal slows the growth of the tumor and helps the immune system overcome some of the tumor’s defenses suggesting it may represent a new target in ovarian cancer.

We demonstrate how cancer cells reprogram normal mesothelial cells into cancer-associated mesothelial cells (CAMC) that have a pro-tumoral function. At the heart of this reprogramming is the reactivation of an important developmental hormone signal, in the form of the anti-Mullerian hormone (AMH), and its receptor AMHR2. While AMHR2 had long been assumed to be expressed by cancer cells, we found that instead cancer-associated mesothelial cells are the tumor cell types that carry this receptor, and that ovarian cancer cells produce its ligand, AMH. We reveal that cancer cells use AMH to control cancer-associated mesothelial cells, by modulating their production of growth factors that promote tumor growth and cytokines that help cloak the tumor from the immune system. This new understanding presents exciting possibilities for therapeutic strategies that aim to neutralize the AMH signal from cancer cells or target the AMHR2 on mesothelial cells to potentially inhibit tumor growth and restore immune response.