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

• Published in: Cell reports (Cambridge) Vol. 42; no. 7; p. 112730
• Main Authors: Chauvin, M., Meinsohn, M.-C., Dasari, S., May, P., Iyer, S., Nguyen, N.M.P., Oliva, E., Lucchini, Z., Nagykery, N., Kashiwagi, A., Mishra, R., Maser, R., Wells, J., Bult, C.J., Mitra, A.K., Donahoe, Patricia K., Pépin, D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2023; Elsevier
• Subjects: AMH; AMHR2; Animals; Anti-Mullerian Hormone - genetics; anti-Müllerian hormone; cancer-associated mesothelial cells; CP: Cancer; Female; Humans; mesothelial; Mice; Mice, Transgenic; ovarian cancer; Ovarian Neoplasms - genetics; Peptide Hormones; Receptors, Transforming Growth Factor beta - metabolism; syngeneic mouse model of ovarian cancer; TGF-β; Tumor Microenvironment; syngeneic mouse model of ovarian cancer; mesothelial; AMHR2; cancer-associated mesothelial cells; ovarian cancer; CP: Cancer; TGF-β; anti-Müllerian hormone; tumor microenvironment; AMH
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112730

Cancer-associated mesothelial cells (CAMCs) in the tumor microenvironment are thought to promote growth and immune evasion. We find that, in mouse and human ovarian tumors, cancer cells express anti-Müllerian hormone (AMH) while CAMCs express its receptor AMHR2, suggesting a paracrine axis. Factors secreted by cancer cells induce AMHR2 expression during their reprogramming into CAMCs in mouse and human in vitro models. Overexpression of AMHR2 in the Met5a mesothelial cell line is sufficient to induce expression of immunosuppressive cytokines and growth factors that stimulate ovarian cancer cell growth in an AMH-dependent way. Finally, syngeneic cancer cells implanted in transgenic mice with Amhr2−/− CAMCs grow significantly slower than in wild-type hosts. The cytokine profile of Amhr2−/− tumor-bearing mice is altered and their tumors express less immune checkpoint markers programmed-cell-death 1 (PD1) and cytotoxic T lymphocyte-associated protein 4 (CTLA4). Taken together, these data suggest that the AMH/AMHR2 axis plays a critical role in regulating the pro-tumoral function of CAMCs in ovarian cancer. [Display omitted] •Cancer-cell-secreted factors reprogram normal omental mesothelial cells to induce AMHR2•AMH secreted by cancer cells modulates cancer-associated mesothelial cell cytokines•The paracrine AMH/AMHR2 axis regulates the pro-tumoral and immune functions of CAMCs•Deletion of Amhr2 in mesothelium reduces ovarian tumor growth and immune exhaustion Cancer cells reprogram normal omental mesothelium into cancer-associated mesothelial cells (CAMCs) by inducing expression of AMHR2. In turn, cancer cells secrete AMH to regulate expression of immunosuppressive cytokines and growth factors by CAMCs. Ovarian tumors implanted in transgenic mice deficient in AMHR2 have a slower growth and reduced immune exhaustion.