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The ERBB-STAT3 axis drives Tasmanian devil facial tumor disease

The ERBB-STAT3 axis drives Tasmanian devil facial tumor disease
The ERBB-STAT3 axis drives Tasmanian devil facial tumor disease

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. Video Abstract:

ERBB, horizontal transmission, MHC class I, receptor tyrosine kinases, STAT3, systems biology, Tasmanian devil, transmissible cancer, tumor vulnerability, xenograft
1535-6108
125-139.e9
Kosack, Lindsay
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Wingelhofer, Bettina
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Popa, Alexandra
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Orlova, Anna
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Agerer, Benedikt
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Vilagos, Bojan
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Majek, Peter
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Parapatics, Katja
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Lercher, Alexander
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Ringler, Anna
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Klughammer, Johanna
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Smyth, Mark
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Khamina, Kseniya
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Baazim, Hatoon
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de Araujo, Elvin D.
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Rosa, David A.
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Park, Jisung
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Tin, Gary
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Ahmar, Siawash
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Gunning, Patrick T.
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Bock, Christoph
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Siddle, Hannah V.
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Woods, Gregory M.
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Kubicek, Stefan
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Murchison, Elizabeth P.
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Bennett, Keiryn L.
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Moriggl, Richard
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Bergthaler, Andreas
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Kosack, Lindsay
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Wingelhofer, Bettina
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Popa, Alexandra
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Orlova, Anna
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Agerer, Benedikt
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Vilagos, Bojan
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Majek, Peter
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Parapatics, Katja
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Lercher, Alexander
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Ringler, Anna
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Klughammer, Johanna
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Smyth, Mark
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Khamina, Kseniya
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Baazim, Hatoon
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de Araujo, Elvin D.
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Rosa, David A.
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Park, Jisung
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Tin, Gary
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Ahmar, Siawash
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Gunning, Patrick T.
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Bock, Christoph
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Siddle, Hannah V.
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Woods, Gregory M.
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Kubicek, Stefan
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Murchison, Elizabeth P.
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Bennett, Keiryn L.
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Moriggl, Richard
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Bergthaler, Andreas
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Kosack, Lindsay, Wingelhofer, Bettina, Popa, Alexandra, Orlova, Anna, Agerer, Benedikt, Vilagos, Bojan, Majek, Peter, Parapatics, Katja, Lercher, Alexander, Ringler, Anna, Klughammer, Johanna, Smyth, Mark, Khamina, Kseniya, Baazim, Hatoon, de Araujo, Elvin D., Rosa, David A., Park, Jisung, Tin, Gary, Ahmar, Siawash, Gunning, Patrick T., Bock, Christoph, Siddle, Hannah V., Woods, Gregory M., Kubicek, Stefan, Murchison, Elizabeth P., Bennett, Keiryn L., Moriggl, Richard and Bergthaler, Andreas (2019) The ERBB-STAT3 axis drives Tasmanian devil facial tumor disease. Cancer Cell, 35 (1), 125-139.e9. (doi:10.1016/j.ccell.2018.11.018).

Record type: Article

Abstract

The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD. Video Abstract:

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Accepted/In Press date: 29 November 2018
e-pub ahead of print date: 14 January 2019
Keywords: ERBB, horizontal transmission, MHC class I, receptor tyrosine kinases, STAT3, systems biology, Tasmanian devil, transmissible cancer, tumor vulnerability, xenograft

Identifiers

Local EPrints ID: 427459
URI: https://eprints.soton.ac.uk/id/eprint/427459
ISSN: 1535-6108
PURE UUID: 2672a0ad-7404-4bbe-a17b-fe291bae7d11

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Date deposited: 17 Jan 2019 17:30
Last modified: 13 Mar 2019 17:38

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Contributors

Author: Lindsay Kosack
Author: Bettina Wingelhofer
Author: Alexandra Popa
Author: Anna Orlova
Author: Benedikt Agerer
Author: Bojan Vilagos
Author: Peter Majek
Author: Katja Parapatics
Author: Alexander Lercher
Author: Anna Ringler
Author: Johanna Klughammer
Author: Mark Smyth
Author: Kseniya Khamina
Author: Hatoon Baazim
Author: Elvin D. de Araujo
Author: David A. Rosa
Author: Jisung Park
Author: Gary Tin
Author: Siawash Ahmar
Author: Patrick T. Gunning
Author: Christoph Bock
Author: Gregory M. Woods
Author: Stefan Kubicek
Author: Elizabeth P. Murchison
Author: Keiryn L. Bennett
Author: Richard Moriggl
Author: Andreas Bergthaler

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