Browsing by Author "Dorado, Jorge"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
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.Publication The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells.(BMJ Publishing Group, 2024-08-08) López-Gil, Juan Carlos; García-Silva, Susana; Ruiz-Cañas, Laura; Navarro, Diego; Palencia-Campos, Adrián; Giráldez-Trujillo, Antonio; Earl, Julie; Dorado, Jorge; Gómez-López, Gonzalo; Monfort-Vengut, Ana; Alcalá, Sonia; Gaida, Matthias M; García-Mulero, Sandra; Cabezas-Sáinz, Pablo; Batres-Ramos, Sandra; Barreto, Emma; Sánchez-Tomero, Patricia; Vallespinós, Mireia; Ambler, Leah; Lin, Meng-Lay; Aicher, Alexandra; García García de Paredes, Ana; de la Pinta, Carolina; Sanjuanbenito, Alfonso; Ruz-Caracuel, Ignacio; Rodríguez-Garrote, Mercedes; Guerra, Carmen; Carrato, Alfredo; de Cárcer, Guillermo; Sánchez, Laura; Nombela-Arrieta, César; Espinet, Elisa; Sanchez-Arevalo Lobo, Víctor Javier; Heeschen, Christopher; Sainz, Bruno; Fundación La Caixa; EMBO Scientific Exchange Fellowship; Juan de la Cierva Formacion; Fero Foundation Grant; Ministerio de Economía y Competitividad (España); Asociación Española Contra el Cáncer; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERONC (Cáncer); Xunta de Galicia (España); University of Zurich; German Research Foundation (DFG); Unión Europea. Comisión Europea. European Research Council (ERC); Fondazione AIRC per la ricerca sul cancro; Shanghai Municipal Education Commission (SHMEC); National Natural Science Foundation of China (NSFC)OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant 'stem-like' cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. DESIGN: We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. RESULTS: Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNF?)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. CONCLUSIONS: This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.