Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer

Tim N. Beck; Vladislav A. Korobeynikov; Alexander E. Kudinov; Rachel Georgopoulos; Nehal R. Solanki; Magda Andrews-Hoke; Timothy M. Kistner; David Pépin; Patricia K. Donahoe; Emmanuelle Nicolas; Margret B. Einarson; Yan Zhou; Yanis Boumber; David A. Proia; Ilya G. Serebriiskii; Erica A. Golemis

doi:10.1016/j.celrep.2016.06.043

Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer

Tim N. Beck, Vladislav A. Korobeynikov, Alexander E. Kudinov, Rachel Georgopoulos, Nehal R. Solanki, Magda Andrews-Hoke, Timothy M. Kistner, David Pépin, Patricia K. Donahoe, Emmanuelle Nicolas, Margret B. Einarson, Yan Zhou, Yanis Boumber, David A. Proia, Ilya G. Serebriiskii, Erica A. Golemis

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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.

Original language	English
Pages (from-to)	657-671
Number of pages	15
Journal	Cell Reports
Volume	16
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2016.06.043
State	Published - Jul 19 2016

Keywords

Animals
Anti-Mullerian Hormone/metabolism
Bone Morphogenetic Protein Receptors, Type II/metabolism
Carcinoma, Non-Small-Cell Lung/metabolism
Cell Plasticity/physiology
Drug Resistance, Neoplasm/physiology
Epithelial Cells/metabolism
Epithelial-Mesenchymal Transition/physiology
Gene Expression Regulation/physiology
Heat-Shock Proteins/metabolism
Lung Neoplasms/metabolism
Mesenchymal Stem Cells/metabolism
Mice
Mice, SCID
NF-kappa B/metabolism
Receptors, Peptide/metabolism
Receptors, Transforming Growth Factor beta/metabolism
Signal Transduction/physiology
Transforming Growth Factor beta/metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.06.043

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Beck, T. N., Korobeynikov, V. A., Kudinov, A. E., Georgopoulos, R., Solanki, N. R., Andrews-Hoke, M., Kistner, T. M., Pépin, D., Donahoe, P. K., Nicolas, E., Einarson, M. B., Zhou, Y., Boumber, Y., Proia, D. A., Serebriiskii, I. G., & Golemis, E. A. (2016). Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer. Cell Reports, 16(3), 657-671. https://doi.org/10.1016/j.celrep.2016.06.043

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title = "Anti-M{\"u}llerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer",

abstract = "Anti-M{\"u}llerian 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.",

keywords = "Animals, Anti-Mullerian Hormone/metabolism, Bone Morphogenetic Protein Receptors, Type II/metabolism, Carcinoma, Non-Small-Cell Lung/metabolism, Cell Plasticity/physiology, Drug Resistance, Neoplasm/physiology, Epithelial Cells/metabolism, Epithelial-Mesenchymal Transition/physiology, Gene Expression Regulation/physiology, Heat-Shock Proteins/metabolism, Lung Neoplasms/metabolism, Mesenchymal Stem Cells/metabolism, Mice, Mice, SCID, NF-kappa B/metabolism, Receptors, Peptide/metabolism, Receptors, Transforming Growth Factor beta/metabolism, Signal Transduction/physiology, Transforming Growth Factor beta/metabolism",

author = "Beck, {Tim N.} and Korobeynikov, {Vladislav A.} and Kudinov, {Alexander E.} and Rachel Georgopoulos and Solanki, {Nehal R.} and Magda Andrews-Hoke and Kistner, {Timothy M.} and David P{\'e}pin and Donahoe, {Patricia K.} and Emmanuelle Nicolas and Einarson, {Margret B.} and Yan Zhou and Yanis Boumber and Proia, {David A.} and Serebriiskii, {Ilya G.} and Golemis, {Erica A.}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = jul,

day = "19",

doi = "10.1016/j.celrep.2016.06.043",

language = "English",

volume = "16",

pages = "657--671",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "3",

}

Beck, TN, Korobeynikov, VA, Kudinov, AE, Georgopoulos, R, Solanki, NR, Andrews-Hoke, M, Kistner, TM, Pépin, D, Donahoe, PK, Nicolas, E, Einarson, MB , Zhou, Y, Boumber, Y, Proia, DA, Serebriiskii, IG & Golemis, EA 2016, 'Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer', Cell Reports, vol. 16, no. 3, pp. 657-671. https://doi.org/10.1016/j.celrep.2016.06.043

TY - JOUR

T1 - Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer

AU - Beck, Tim N.

AU - Korobeynikov, Vladislav A.

AU - Kudinov, Alexander E.

AU - Georgopoulos, Rachel

AU - Solanki, Nehal R.

AU - Andrews-Hoke, Magda

AU - Kistner, Timothy M.

AU - Pépin, David

AU - Donahoe, Patricia K.

AU - Nicolas, Emmanuelle

AU - Einarson, Margret B.

AU - Zhou, Yan

AU - Boumber, Yanis

AU - Proia, David A.

AU - Serebriiskii, Ilya G.

AU - Golemis, Erica A.

PY - 2016/7/19

Y1 - 2016/7/19

N2 - 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.

AB - 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.

KW - Animals

KW - Anti-Mullerian Hormone/metabolism

KW - Bone Morphogenetic Protein Receptors, Type II/metabolism

KW - Carcinoma, Non-Small-Cell Lung/metabolism

KW - Cell Plasticity/physiology

KW - Drug Resistance, Neoplasm/physiology

KW - Epithelial Cells/metabolism

KW - Epithelial-Mesenchymal Transition/physiology

KW - Gene Expression Regulation/physiology

KW - Heat-Shock Proteins/metabolism

KW - Lung Neoplasms/metabolism

KW - Mesenchymal Stem Cells/metabolism

KW - Mice

KW - Mice, SCID

KW - NF-kappa B/metabolism

KW - Receptors, Peptide/metabolism

KW - Receptors, Transforming Growth Factor beta/metabolism

KW - Signal Transduction/physiology

KW - Transforming Growth Factor beta/metabolism

UR - http://www.scopus.com/inward/record.url?scp=84989887233&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.06.043

DO - 10.1016/j.celrep.2016.06.043

M3 - Article

C2 - 27396341

SN - 2211-1247

VL - 16

SP - 657

EP - 671

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

Anti-Müllerian Hormone Signaling Regulates Epithelial Plasticity and Chemoresistance in Lung Cancer

Abstract

Keywords

UN SDGs

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