title: Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer.
abstract: Anti-Müllerian hormone (AMH) and its type II receptor AMHR2, both previously thought to primarily function in gonadal tissue, were unexpectedly identified as potent regulators of transforming growth factor (TGF-β)/bone morphogenetic protein (BMP) signaling and epithelial-mesenchymal transition (EMT) in lung cancer. AMH is a TGF-β/BMP superfamily member, and AMHR2 heterodimerizes with type I receptors (ALK2, ALK3) also used by the type II receptor for BMP (BMPR2). AMH signaling regulates expression of BMPR2, ALK2, and ALK3, supports protein kinase B-nuclear factor κB (AKT-NF-κB) and SMAD survival signaling, and influences BMP-dependent signaling in non-small cell lung cancer (NSCLC). AMH and AMHR2 are selectively expressed in epithelial versus mesenchymal cells, and loss of AMH/AMHR2 induces EMT. Independent induction of EMT reduces expression of AMH and AMHR2. Importantly, EMT associated with depletion of AMH or AMHR2 results in chemoresistance but sensitizes cells to the heat shock protein 90 (HSP90) inhibitor ganetespib. Recognition of this AMH/AMHR2 axis helps to further elucidate TGF-β/BMP resistance-associated signaling and suggests new strategies for therapeutic targeting of EMT.
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Tim N
authors.initials: TN
authors.lastname: Beck
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Medical Department, Novosibirsk State University, Novosibirsk 630090, Russia.
authors.forename: Vladislav A
authors.initials: VA
authors.lastname: Korobeynikov
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Kudinov
authors.affiliation: Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Georgopoulos
authors.affiliation: Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Program in Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Nehal R
authors.initials: NR
authors.lastname: Solanki
authors.affiliation: Yale University, New Haven, CT 06520, USA.
authors.forename: Magda
authors.initials: M
authors.lastname: Andrews-Hoke
authors.affiliation: Johns Hopkins University, Baltimore, MD 21218, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Kistner
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pépin
authors.affiliation: Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Department of Surgery, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Margret B
authors.initials: MB
authors.lastname: Einarson
authors.affiliation: Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA 19140, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Yanis
authors.initials: Y
authors.lastname: Boumber
authors.affiliation: Synta Pharmaceuticals, Lexington, MA 02421, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Kazan Federal University, 420000 Kazan, Russian Federation.
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Serebriiskii
authors.affiliation: Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Program in Molecular and Cell Biology and Genetics, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address: erica.golemis@fccc.edu.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D000066670:Cell Plasticity / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism* / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D018000:Receptors, Peptide / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D006360:Heat-Shock Proteins; D016328:NF-kappa B; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C084621:anti-Mullerian hormone receptor; D054304:Anti-Mullerian Hormone; D052006:Bone Morphogenetic Protein Receptors, Type II