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Sökning: id:"swepub:oai:DiVA.org:umu-206023" > LAMC2 regulates key...

LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth

Erice, Oihane (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
Narayanan, Shruthi (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain
Feliu, Iker (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
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Entrialgo-Cadierno, Rodrigo (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
Malinova, Antonia (författare)
Department of Diagnostics and Public Health, University of Verona, Verona, Italy
Vicentini, Caterina (författare)
Department of Diagnostics and Public Health, University of Verona, Verona, Italy
Guruceaga, Elizabeth (författare)
IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; University of Navarra, Center for Applied Medical Research, Computational Biology Program, Pamplona, Spain
Delfino, Pietro (författare)
Department of Diagnostics and Public Health, University of Verona, Verona, Italy
Trajkovic-Arsic, Marija (författare)
Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany
Moreno, Haritz (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
Valencia, Karmele (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
Blanco, Ester (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
Macaya, Irati (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain
Öhlund, Daniel, 1979- (författare)
Umeå universitet,Institutionen för strålningsvetenskaper,Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)
Khatri, Purvesh (författare)
Stanford Institute for Immunity, Transplantation and Infection, CA, Stanford, United States; Stanford Center for Biomedical Informatics Research, Department of Medicine, Stanford University, CA, Stanford, United States
Lecanda, Fernando (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Pathology, Anatomy, Physiology, University of Navarra, Pamplona, Spain
Scarpa, Aldo (författare)
Department of Diagnostics and Public Health, University of Verona, Verona, Italy; ARC-Net Research Center, University of Verona, Verona, Italy
Siveke, Jens T. (författare)
Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK, partner site University Hospital Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany
Corbo, Vincenzo (författare)
Department of Diagnostics and Public Health, University of Verona, Verona, Italy
Ponz-Sarvise, Mariano (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain
Vicent, Silve (författare)
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Department of Pathology, Anatomy, Physiology, University of Navarra, Pamplona, Spain
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 (creator_code:org_t)
American Association for Cancer Research (AACR), 2023
2023
Engelska.
Ingår i: Clinical Cancer Research. - : American Association for Cancer Research (AACR). - 1078-0432 .- 1557-3265. ; 29:6, s. 1137-1154
Relaterad länk:
https://urn.kb.se/re...
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https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • PURPOSE: The identification of pancreatic ductal adenocarcinoma (PDAC) dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here, we investigated the cellular, functional, and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies.EXPERIMENTAL DESIGN: LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA-sequencing, and publicly available gene expression datasets from experimental and clinical studies examined to query its human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated.RESULTS: LAMC2 was consistently upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors (MEK1/2i). A LAMC2-regulated network was featured in PDAC, including both classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a functional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2is that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids.CONCLUSIONS: LAMC2 is a molecular target in PDAC that regulates a transcriptional network that unveils a dual drug combination for cancer treatment.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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