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

M Chauvin; M-C Meinsohn; S Dasari; P May; S Iyer; N M P Nguyen; E Oliva; Z Lucchini; N Nagykery; A Kashiwagi; R Mishra; R Maser; J Wells; C J Bult; A K Mitra; Patricia K Donahoe; D Pépin

doi:10.1016/j.celrep.2023.112730

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

Cell Rep. 2023 Jul 25;42(7):112730. doi: 10.1016/j.celrep.2023.112730. Epub 2023 Jul 14.

Authors

M Chauvin¹, M-C Meinsohn¹, S Dasari², P May³, S Iyer⁴, N M P Nguyen¹, E Oliva⁵, Z Lucchini³, N Nagykery¹, A Kashiwagi¹, R Mishra⁴, R Maser⁶, J Wells⁶, C J Bult⁶, A K Mitra², Patricia K Donahoe¹, D Pépin⁷

Affiliations

¹ Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA.
² Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA.
³ Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
⁴ Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
⁵ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME, USA.
⁷ Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA; Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME, USA. Electronic address: DPEPIN@mgh.harvard.edu.

PMID: 37453057
DOI: 10.1016/j.celrep.2023.112730

Abstract

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.

Keywords: AMH; AMHR2; CP: Cancer; TGF-β; anti-Müllerian hormone; cancer-associated mesothelial cells; mesothelial; ovarian cancer; syngeneic mouse model of ovarian cancer; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-Mullerian Hormone / genetics
Female
Humans
Mice
Mice, Transgenic
Ovarian Neoplasms* / genetics
Peptide Hormones*
Receptors, Transforming Growth Factor beta / metabolism
Tumor Microenvironment

Substances

Anti-Mullerian Hormone
Peptide Hormones
Receptors, Transforming Growth Factor beta

Grants and funding

R01 HD102014/HD/NICHD NIH HHS/United States