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LAMC2 regulates key transcriptional and targetable effectors to support pancreatic cancer growth
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain; Medical Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain.
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain.
University of Navarra, Center for Applied Medical Research, Program in Solid Tumors, Pamplona, Spain.
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2023 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 29, no 6, p. 1137-1154Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Association for Cancer Research (AACR) , 2023. Vol. 29, no 6, p. 1137-1154
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-206023DOI: 10.1158/1078-0432.CCR-22-0794ISI: 000996642100001PubMedID: 36607777Scopus ID: 2-s2.0-85150225593OAI: oai:DiVA.org:umu-206023DiVA, id: diva2:1746333
Available from: 2023-03-28 Created: 2023-03-28 Last updated: 2023-09-05Bibliographically approved

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Öhlund, Daniel

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