Abstract 6041: LAMC2 as a therapeutic target in pancreatic ductal adenocarcinoma

Abstract

Abstract BACKGROUND. Pancreatic cancer stands as one of the deadliest tumors, in part due to the limited efficacy of currently existing therapies. Pancreatic ductal adenocarcinoma (PDAC) represents the predominant subtype (around 85% of total cases), where KRAS is the most frequently mutated oncogene. Tumor microenvironment in PDAC is characterized by a desmoplastic stroma which is composed, among other molecules, of collagens of different types, fibronectin and laminins. A member of the laminin family, LAMININ γ2 or LAMC2, was previously identified by our group as part of a cross-tumors KRAS signature whose high expression was a marker of poor survival in PDAC patients. Given the relevant functional implication of other members of the cross-tumors KRAS signature in PDAC, we aimed to investigate the role of LAMC2 in this tumor type. METHODS. A meta-analysis of several human PDAC data sets (n=6) and survival analysis of the TCGA data were performed to query the expression levels and prognosis significance of LAMC2. Human and mouse PDAC cell lines as well as a mouse model of PDAC (Kras, Tp53f/f, Ptf1aCre) were used to assess LAMC2 expression. In vitro (2D and 3D organoids) and in vivo models derived from human and mouse PDAC cell lines or primary tumors were used to define the functional role of LAMC2 in PDAC. Lastly, cellular and molecular analysis were deployed to dissect the mechanism of action of LAMC2 in PDAC. RESULTS. At the clinical level, we have observed that LAMC2 is overexpressed in human PDAC patients with regard to normal tissue and that its high levels identify the group of patients with the worst survival. The overexpression of LAMC2 was recapitulated in human and mouse cell lines. Genetic depletion of LAMC2 had an adverse effect in 2D proliferation, clonogenic efficiency, 3D organoid growth, and PDAC-based xenograft/allograft tumor development. This deleterious effect is driven by an induction in apoptosis and a decrease in S phase consistent across species. Mechanistically, LAMC2 is mainly linked to the KRAS pathway through ERK1/2 and is transcriptionally regulated by the transcription factor FOSL1/AP1, which was also a member of the cross-tumors signature. These data suggest that LAMC2 is involved in the control of different functions related to the PDAC phenotype induced by KRAS. CONCLUSION. LAMC2 is a molecular target in PDAC with clinical implications based on the potential development of new therapeutic and diagnostic strategies for PDAC patients. Citation Format: Oihane Erice, Ester Blanco, Karmele Valencia, Elizabeth Guruceaga, Haritz Moreno, Fernando Lecanda, Vincenzo Corbo, Daniel Ölund, Mariano Ponz-Sarvise, Vicent Silve. LAMC2 as a therapeutic target in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6041.