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Wilms tumor (WT) is an embryonal malignant neoplasm of the kidney that accounts for 6–7% of all childhood cancers. WT seems to derive from multipotent embryonic renal stem cells that have failed to differentiate properly. Since mechanisms underlying WT tumorigenesis remain largely unknown, the aim of this study was to explore the expression of embryonic stem cell (ESC) markers in samples of WT patients after chemotherapy treatment SIOP protocol, as the gene expression patterns of ESC are like those of most cancer cells. We found that expression of ESC markers is heterogeneous, and depends on histological WT components. Interestingly, among ESC markers, HMGA2 was expressed significantly stronger in the blastemal component than in the stromal and the normal kidney. Moreover, two subsets of patients of WT blastemal type were identified, depending on the expression levels of HMGA2. High HMGA2 expression levels were significantly associated with a higher proliferation rate (p=0.0345) and worse patient prognosis (p=0.0289). The expression of HMGA2 was a stage-independent factor of clinical outcome in blastemal WT patients. Our multivariate analyses demonstrated the association between LIN28B–LET7A–HMGA2 expression, and the positive correlation between HMGA2 and SLUG expression (p=0.0358) in blastemal WT components. In addition, patients with a poor prognosis and high HMGA2 expression presented high levels of MDR3 (multidrug resistance transporter). Our findings suggest that HMGA2 plays a prominent role in the pathogenesis of a subset of blastemal WT, strongly associated with relapse and resistance to chemotherapy., LHP and DJGD are supported by Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0017). CS is supported by a contract from Nicolás Monardes Program, Consejería de Salud, Junta de Andalucía. Research in Enrique de Alava’s lab is supported by the Ministry of Economy and Competitiveness of Spain-FEDER (CIBERONC, PI1700464, RD06/0020/0059, FMGE) and the European Commission (FP7-HEALTH-2011-two-stage, Project ID 278742 EUROSARC). DJGD is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016). Research in Carmen Sáez’s lab is also supported by research grants from the Instituto de Salud Carlos III, FIS PI13/02282.

The presence of the chimeric EWSR1-FLI1 oncoprotein is the main and initiating event defining Ewing sarcoma (ES). The dysregulation of epigenomic and proteomic homeostasis induced by the oncoprotein contributes to a wide variety of events involved in oncogenesis and tumor progression. Attempts at studying the effects of EWSR1-FLI1 in non-tumor cells to understand the mechanisms underlying sarcomagenesis have been unsuccessful to date, as ectopic expression of EWSR1-FLI1 blocks cell cycle progression and induces apoptosis in the tested cell lines. Therefore, it is essential to find a permissive cell type for EWSR1-FLI1 expression that allows its endogenous molecular functions to be studied. Here we have demonstrated that HeLa cell lines are permissive to EWSR1-FLI1 ectopic expression, and that our model substantially recapitulates the endogenous activity of the EWSR1-FLI1 fusion protein. This model could contribute to better understanding ES sarcomagenesis by helping to understand the molecular mechanisms induced by the EWSR1-FLI1 oncoprotein., Research in the EDA lab is supported by Asociación Española Contra el Cáncer (AECC). Enrique de Alava’s lab is also supported by the Ministry of Economy and Competitiveness of Spain-FEDER (CIBERONC, PI11700464, RD06/0020/0059) and the European Commission (FP7-HEALTH-2011-two-stage, Project ID278742 EUROSARC). DGD and LHP are supported by CIBERONC (CB16/12/00361). DGD is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016). LHP is a PhD researcher funded by the Consejería de Salud, Junta de Andalucía (PI-0013-2018). The funder Vitro SA provided support in the form of salaries for the author CM but had no additional roles in the study design, data collection, data analyses, decision to publish or manuscript preparation. The specific roles of this author (CM) are articulated in the ‘author contributions’ section.