Browsing by Author "Cioffi, Michele"
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Publication Mast cells impair melanoma cell homing and metastasis by inhibiting HMGA1 secretion.(Wiley, 2023-02) Benito-Martin, Alberto; Nogués, Laura; Hergueta-Redondo, Marta; Castellano-Sanz, Elena; Garvin, Eduardo; Cioffi, Michele; Sola-Castrillo, Paloma; Buehring, Weston; Ximénez-Embún, Pilar; Muñoz, Javier; Matei, Irina; Villanueva, Josep; Peinado Selgas, Hector; United States Department of Health and Human Services; Children's Cancer and Blood Foundation; Feldestein Foundation; Melanoma Research Alliance; Nancy C. and Daniel P. Paduano Foundation; Starr FoundationMetastatic disease is the major cause of death from cancer. From the primary tumour, cells remotely prepare the environment of the future metastatic sites by secreted factors and extracellular vesicles. During this process, known as pre-metastatic niche formation, immune cells play a crucial role. Mast cells are haematopoietic bone marrow-derived innate immune cells whose function in lung immune response to invading tumours remains to be defined. We found reduced melanoma lung metastasis in mast cell-deficient mouse models (Wsh and MCTP5-Cre-RDTR), supporting a pro-metastatic role for mast cells in vivo. However, due to evidence pointing to their antitumorigenic role, we studied the impact of mast cells in melanoma cell function in vitro. Surprisingly, in vitro co-culture of bone-marrow-derived mast cells with melanoma cells showed that they have an intrinsic anti-metastatic activity. Mass spectrometry analysis of melanoma-mast cell co-cultures secretome showed that HMGA1 secretion by melanoma cells was significantly impaired. Consistently, HMGA1 knockdown in B16-F10 cells reduced their metastatic capacity in vivo. Importantly, analysis of HMGA1 expression in human melanoma tumours showed that metastatic tumours with high HMGA1 expression are associated with reduced overall and disease-free survival. Moreover, we show that HMGA1 is reduced in the nuclei and enriched in the cytoplasm of melanoma metastatic lesions when compared to primary tumours. These data suggest that high HMGA1 expression and secretion from melanoma cells promote metastatic behaviour. Targeting HMGA1 expression intrinsically or extrinsically by mast cells actions reduce melanoma metastasis. Our results pave the way to the use of HMGA1 as anti-metastatic target in melanoma as previously suggested in other cancer types.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.