Clinical Implications and Molecular Features of Extracellular Matrix Networks in Soft Tissue Sarcomas

Author:

Pankova Valeriya1ORCID,Krasny Lukas1ORCID,Kerrison William1ORCID,Tam Yuen B.1ORCID,Chadha Madhumeeta1ORCID,Burns Jessica1ORCID,Wilding Christopher P.1ORCID,Chen Liang23ORCID,Chowdhury Avirup1ORCID,Perkins Emma1ORCID,Lee Alexander T.J.4ORCID,Howell Louise5ORCID,Guljar Nafia1ORCID,Sisley Karen6ORCID,Fisher Cyril7ORCID,Chudasama Priya23ORCID,Thway Khin18ORCID,Jones Robin L.89ORCID,Huang Paul H.1ORCID

Affiliation:

1. Division of Molecular Pathology, The Institute of Cancer Research, London, United Kingdom. 1

2. Precision Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. 2

3. National Center for Tumor Diseases, Heidelberg, Germany. 3

4. The Christie NHS Foundation Trust, Manchester, United Kingdom. 4

5. Light Microscopy Facility, The Institute of Cancer Research, London, United Kingdom. 5

6. Division of Clinical Medicine, The Medical School, University of Sheffield, Sheffield, United Kingdom. 6

7. University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom. 7

8. The Royal Marsden NHS Foundation Trust, London, United Kingdom. 8

9. Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom. 9

Abstract

Abstract Purpose: The landscape of extracellular matrix (ECM) alterations in soft tissue sarcomas (STS) remains poorly characterized. We aimed to investigate the tumor ECM and adhesion signaling networks present in STS and their clinical implications. Experimental Design: Proteomic and clinical data from 321 patients across 11 histological subtypes were analyzed to define ECM and integrin adhesion networks. Subgroup analysis was performed in leiomyosarcomas (LMS), dedifferentiated liposarcomas (DDLPS), and undifferentiated pleomorphic sarcomas (UPS). Results: This analysis defined subtype-specific ECM profiles including enrichment of basement membrane proteins in LMS and ECM proteases in UPS. Across the cohort, we identified three distinct coregulated ECM networks which are associated with tumor malignancy grade and histological subtype. Comparative analysis of LMS cell line and patient proteomic data identified the lymphocyte cytosolic protein 1 cytoskeletal protein as a prognostic factor in LMS. Characterization of ECM network events in DDLPS revealed three subtypes with distinct oncogenic signaling pathways and survival outcomes. Evaluation of the DDLPS subtype with the poorest prognosis nominates ECM remodeling proteins as candidate antistromal therapeutic targets. Finally, we define a proteoglycan signature that is an independent prognostic factor for overall survival in DDLPS and UPS. Conclusions: STS comprise heterogeneous ECM signaling networks and matrix-specific features that have utility for risk stratification and therapy selection, which could in future guide precision medicine in these rare cancers.

Funder

Sarcoma UK

Cancer Research UK

NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research

Royal Marsden Cancer Charity

Institute of Cancer Research

German Research Foundation

German Federal Ministry of Education

Sarcoma Foundation of America

Publisher

American Association for Cancer Research (AACR)

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