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
Affiliations
M. Chauvin
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
M.-C. Meinsohn
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
S. Dasari
Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
P. May
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA
S. Iyer
Whitehead Institute for Biomedical Research, Cambridge, MA, USA
N.M.P. Nguyen
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
E. Oliva
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
Z. Lucchini
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA
N. Nagykery
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
A. Kashiwagi
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
R. Mishra
Whitehead Institute for Biomedical Research, Cambridge, MA, USA
R. Maser
Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME, USA
J. Wells
Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME, USA
C.J. Bult
Mouse Genome Informatics, The Jackson Laboratory, Bar Harbor, ME, USA
A.K. Mitra
Indiana University School of Medicine-Bloomington, Indiana University, Bloomington, IN, USA
Patricia K. Donahoe
Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA; Department of Surgery, Harvard Medical School, Boston, MA, USA
D. Pépin
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; Corresponding author
Summary: 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.
