Browsing by Author "Trabulo, Sara M."
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Publication MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3(Cell Press, 2015) Cioffi, Michele; Vallespinos-Serrano, Mireia; Trabulo, Sara M.; Jose Fernandez-Marcos, Pablo; Firment, Ashley N.; Vazquez, Berta N.; Vieira, Catarina R.; Mulero, Francisca; Camara, Juan A.; Cronin, Ultan P.; Perez, Manuel; Soriano, Joaquim; Galvez, Beatriz G.; Castells-Garcia, Alvaro; Haage, Verena; Raj, Deepak; Megias Vazquez, Diego; Hahn, Stephan; Serrano, Lourdes; Moon, Anne; Aicher, Alexandra; Heeschen, Christopher; European Commission; Unión Europea. Comisión Europea. 7 Programa Marco; Fundación La CaixaConquering obesity has become a major socioeconomic challenge. Here, we show that reduced expression of the miR-25-93-106b cluster, or miR-93 alone, increases fat mass and, subsequently, insulin resistance. Mechanistically, we discovered an intricate interplay between enhanced adipocyte precursor turnover and increased adipogenesis. First, miR-93 controls Tbx3, thereby limiting self-renewal in early adipocyte precursors. Second, miR-93 inhibits the metabolic target Sirt7, which we identified as a major driver of in vivo adipogenesis via induction of differentiation and maturation of early adipocyte precursors. Using mouse parabiosis, obesity in mir-25-93-106b(-/-) mice could be rescued by restoring levels of circulating miRNA and subsequent inhibition of Tbx3 and Sirt7. Downregulation of miR-93 also occurred in obese ob/ob mice, and this phenocopy of mir-25-93-106b(-/-) was partially reversible with injection of miR-93 mimics. Our data establish miR-93 as a negative regulator of adipogenesis and a potential therapeutic option for obesity and the metabolic syndrome.Publication The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells(BMJ Publishing Group, 2015) Cioffi, Michele; Trabulo, Sara M.; Sanchez-Ripoll, Yolanda; Miranda-Lorenzo, Irene; Lonardo, Enza; Dorado, Jorge; Reis Vieira, Catarina; Ramirez, Juan Carlos; Hidalgo, Manuel; Aicher, Alexandra; Hahn, Stephan; Sainz, Jr., Bruno; Heeschen, Christopher; Unión Europea. Comisión Europea. European Research Council (ERC); Unión Europea. Comisión Europea; Ministerio de Economía y Competitividad (España); Instituto de Salud Carlos III; Fundación La CaixaObjective Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. Design Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. Results We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-beta 1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. Conclusions Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.