Search

Drug resistance is one of the major factors associated with poor outcome of cancer patients. Treatment of Ewing sarcoma (EwS), an aggressive neoplasm mainly affecting children, adolescents and young adults, is associated with therapy failure and tumor relapse in 30-80% of the cases. Thus, it supports the need to explore the mechanisms modulating drug activity. Here, we describe a novel mechanism of drug sensitivity based on the role of EWS::FLI1 in R-loop metabolism. Our results demonstrate that EWS::FLI1 promotes R-loop formation favoring the interaction between DHX9 and elongating RNA polymerase II. In addition, we discovered that EWS::FLI1 kidnaps DHX9 preventing the resolution of TOP1 poisoning-associated R-loops. Our findings indicate that R-loops accumulation promotes replicative stress, genome instability and cell sensitivity to SN-38. Collectively, these results uncover a novel mechanism behind EwS sensitivity to genotoxic agents, with relevant implications for EwS treatment.

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease., E.A.’s laboratory is supported by ISCIII-FEDER (PI20/00003), CIBERONC (CB16/12/00361), PAIDI-Junta de Andalucía (P18-RT-735), Fundación CRIS Contra el Cáncer, Asociación Candela Riera and Asociación Pablo Ugarte. A.T.A. is supported by Juan de la Cierva Incorporación fellowship (IJC-2018-036767-I); P.P.-C. is sponsored by the Fundación María García Estrada. J.O.-P is supported by Ph.D. Grant Plan Propio from the University of Seville. J.D.-M is supported by CIBERONC (CB16/12/00361). C.S.-A. is supported by the European Social Fund and the Junta de Andalucía (Talento Doctores 2020, DOC_01473). This work was supported by grants from the Consejería de Salud (Junta de Andalucía, grants No PI-0036-2017, PI-0040-2017, and PI-0061-2020) awarded to J.D.-M, A.T.A. and C. S.-A., respectively. This work was also supported by the GEIS-Fundación Mari Paz Jiménez Casado (IV beca trienal) granted to J.D.-M, the 13ª GEIS-Beca Buesa granted to A.T.A. and CRIS (Cancer Research Innovation Spain) granted to J.D.-M and E.A. The laboratory of T.G.P.G. is supported by the Barbara and Wilfried Mohr Foundation. The lab of J.A. is supported by the Instituto de Salud Carlos III (ISCIII), grant number PI20CIII/00020; Asociación Pablo Ugarte, grant numbers TRPV205/18, TPI-M 1149/13; Asociación Candela Riera; Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant reference: TVP333-19.

Tumor growth depends on the vascular system, either through the expansion of blood vessels or novel adaptation by tumor cells. One of these novel pathways is vasculogenic mimicry (VM), which is defined as a tumor-provided vascular system apart from endothelial cell-lined vessels, and its origin is partly unknown. It involves highly aggressive tumor cells expressing endothelial cell markers that line the tumor irrigation. VM has been correlated with high tumor grade, cancer cell invasion, cancer cell metastasis, and reduced survival of cancer patients. In this review, we summarize the most relevant studies in the field of angiogenesis and cover the various aspects and functionality of aberrant angiogenesis by tumor cells. We also discuss the intracellular signaling mechanisms involved in the abnormal presence of VE-cadherin (CDH5) and its role in VM formation. Finally, we present the implications for the paradigm of tumor angiogenesis and how targeted therapy and individualized studies can be applied in scientific analysis and clinical settings.