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^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

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

49 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 (US)
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

Funding

We thank Drs. Jonathan Chernoff, Jeffrey Peterson, Mauricio Reginato, and Mark Lemmon for critical reading of the manuscript. We also thank current and former members of the E.A.G. lab, and the facilities and our colleagues at Fox Chase Cancer Center. Jean-Marc Barret and Jean-François Prost from GamaMabs Pharma deserve special thanks for generously sharing reagents and ideas. The authors were supported by U54 CA149147, R21 CA181287, R21 CA191425, and P50 CA083638 from the NIH (to E.A.G.), the Ruth L. Kirschstein NRSA F30 fellowship (F30 CA180607) from the NIH (to T.N.B.), NCI Core Grant P30 CA006927 (to Fox Chase Cancer Center), the Russian Ministry of Science and Education, as task #17.1891.2014/K (to V.A.K.), and the Russian Government to support the Program for Competitive Growth of Kazan Federal University (to I.G.S.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

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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.",

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 (US)",

volume = "16",

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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

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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.

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

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UN SDGs

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