GARP promotes the proliferation and therapeutic resistance of bone sarcoma cancer cells through the activation of TGF-β

Abstract

Sarcomas are mesenchymal cancers with poor prognosis, representing about 20% of all solid malignancies in children, adolescents, and young adults. Radio- and chemoresistance are common features of sarcomas warranting the search for novel prognostic and predictive markers. GARP/LRRC32 is a TGF-β-activating protein that promotes immune escape and dissemination in various cancers. However, if GARP affects the tumorigenicity and treatment resistance of sarcomas is not known. We show that GARP is expressed by human osteo-, chondro-, and undifferentiated pleomorphic sarcomas and is associated with a significantly worse clinical prognosis. Silencing of GARP in bone sarcoma cell lines blocked their proliferation and induced apoptosis. In contrast, overexpression of GARP promoted their growth in vitro and in vivo and increased their resistance to DNA damage and cell death induced by etoposide, doxorubicin, and irradiation. Our data suggest that GARP could serve as a marker with therapeutic, prognostic, and predictive value in sarcoma. We propose that targeting GARP in bone sarcomas could reduce tumour burden while simultaneously improving the efficacy of chemo- and radiotherapy. ; Instituto de Salud Carlos III ; European Union (EU) PI15/00794 PI18/00826 CPII15/00032 PI15/02015 ; Junta de Andalucía C-0013-2018 ; Spanish Government PEJ-2014-A-46314 ; Agencia Estatal de Investigación (AEI) [MICINN/Fondo Europeo de Desarrollo Regional (FEDER)] SAF-2016-75286-R ; ISCIII/FEDER [Miguel Servet Program] CPII16/00049 ; ISCIII/FEDER [Sara Borrell Program] CD16/00103 ; Servicio de Salud del Principado de Asturias, Instituto de Salud Carlos III PT17/0015/0023 ; Fundación Bancaria Cajastur PT17/0015/0023 ; ISCIII/FEDER [Consorcio CIBERONC] CB16/12/00390