Suppl. Figure 1. A. Association analysis of LAMC2 expression with clinical variables using quartile 1 of H score (23.2) as cut-off. B. Correlation of LAMC2 expression and tumor volume in a tissue array of 119 PDAC samples. C and D. Survival analysis stratified by LAMC2 expression from ICGC and TCGA datasets.
Funding
Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España (MINECO)
ITN Program 2020
Departamento de Salud, Gobierno de Navarra (Department of Health, Government of Navarra)
Associazione Italiana per la Ricerca sul Cancro (AIRC)
National Cancer Institute
Ministerio de Ciencia e Innovación (MICINN)
ARTICLE ABSTRACT
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.
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.
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.
LAMC2 is a molecular target in PDAC that regulates a transcriptional network that unveils a dual drug combination for cancer treatment.
