Dataset Information

The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease

ABSTRACT: The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the culprit molecular underpinnings, we designed an approach that combines sensitivity to drugs with an integrated systems-biology characterization. Sensitivity to inhibitors of the ERBB family of receptor tyrosine kinases correlated with their overexpression, suggesting a causative link. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to oncogenic signaling hubs including evolutionary conserved STAT3. Indeed, inhibition of ERBB blocked phosphorylation of STAT3 and arrested cancer cells. Blockade of ERBB signaling prevented tumor growth in a xenograft model and resulted in recovery of MHC-I gene expression. This link between the hyperactive ERBB-STAT3 axis and decreased MHC-I mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and lets us propose a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD.

OTHER RELATED OMICS DATASETS IN: GSE108107GSE108160

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Sarcophilus Harrisii

TISSUE(S): Spleen, Skin

SUBMITTER: Alexandra Popa

LAB HEAD: Dr Andreas Bergthaler

PROVIDER: PXD009283 | Pride | 2019-01-18

REPOSITORIES: Pride

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			Action	DRS
	M559-B01-O329-SH-P7928-1.raw	Raw
	M559-B02-O329-SH-P7928-1.raw	Raw
	M559-B03-O329-SH-P7928-1.raw	Raw
	M559-B04-O329-SH-P7928-1.raw	Raw
	M559-B05-O329-SH-P7928-1.raw	Raw

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The ERBB-STAT3 Axis Drives Tasmanian Devil Facial Tumor Disease.

Kosack Lindsay L Wingelhofer Bettina B Popa Alexandra A Orlova Anna A Agerer Benedikt B Vilagos Bojan B Majek Peter P Parapatics Katja K Lercher Alexander A Ringler Anna A Klughammer Johanna J Smyth Mark M Khamina Kseniya K Baazim Hatoon H de Araujo Elvin D ED Rosa David A DA Park Jisung J Tin Gary G Ahmar Siawash S Gunning Patrick T PT Bock Christoph C Siddle Hannah V HV Woods Gregory M GM Kubicek Stefan S Murchison Elizabeth P EP Bennett Keiryn L KL Moriggl Richard R Bergthaler Andreas A

Cancer cell 20190101 1

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. ...[more]

PMID: 30645971

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Project description:Background Skeletal morbidity in cancer patients has a major impact on quality of life and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune-checkpoint inhibitors (ICI) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICI on bone turnover by longitudinal assessment of bone turnover markers (BTM) in cancer patients and by validation in a novel bioengineered 3D model of bone remodeling. Methods Serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-propeptide, PINP; and osteocalcin, OCN) were measured before each ICI application (PD1 inhibitors, PD1i or PD-L1 inhibitors, PD1i) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation upon treatment with ICI. In addition, their effect on bone remodeling was assessed by immunohistochemistry, immunofluorescence and proteomics analysis in a dynamic 3D model of the bone multicellular unit (BMU). Results The longitudinal assessment of BTM revealed a significant decrease in CTX levels after 3 weeks, followed by a return to baseline levels within 3 months. In contrast, serum levels of PINP and OCN gradually increased from baseline to the last postbaseline assessment. In vitro, ICI impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling, but not JNK, ERK and AKT; while lacking any direct effect on osteogenesis. However, using our novel bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity upon ICI treatment by demonstrating impaired OC maturation along with increased OB differentiation. Conclusion Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with the OB/OC coupling of bone turnover and may potentially exert a protective effect on bone by impairing the differentiation OCs and indirectly promoting osteogenesis.