Abstract PO-038: LAMC2: New player in stemness and tumor progression in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating and essentially incurable disease, typically characterized by high chemoresistance and metastatic spread attributable to cancer stem cells (CSCs). This subpopulation is critical for tumor initiation and recurrence, but the mechanism through which they acquire metastatic traits is not well understood. Hence, targeting the CSC niche and their plasticity could be a complementary therapeutic strategy against cancer. Laminin subunit-γ-2 (LAMC2) is an epithelial basement membrane protein, which controls cell motility and adhesion and is widely expressed in the majority of human tumors. However, its role in PDAC remains largely unknown. In several patient cohorts we observed that high levels of LAMC2 significantly correlated with shorter overall survival. In addition, the tissue microarray analysis on PDAC sections revealed prognostic significance of LAMC2 expression in tumor with high grade of aggressiveness (i.e., G2 and G3). To determine the role of LAMC2 in sustaining tumorigenicity, we knocked down it in patient-derived xenografts (PDX) cells using lentiviral shRNA constructs. The silencing of LAMC2 resulted in decreased self-renewal, invasiveness, tumorigenicity and gemcitabine resistance both in vitro and in vivo. To identify or track the LAMC2 tumor cell population in an intact environment we engineered primary PDAC cells that carry EGFP cassette knocked in the LAMC2 locus through the CRISPR-Cas9 technique. Analysis of LAMC2-EGFP+ cells isolated from tumor demonstrated that these cells express a gene program similar to that of highly metastatic stem cells and that they initiate and propagate both the primary tumor and the metastasis to recipient mice very efficiently compared to their counterpart. In conclusion, we identified a highly metastatic subpopulation of cancer stem cells, characterized by high levels of LAMC2. Strategies aimed at targeting the LAMC2 population may be effective in reducing tumor aggressiveness in combination with conventional therapy. Citation Format: Donatella Delle Cave, Tea Teresa Iavazzo, Maria Mangini, Gennaro Andolfi, Teresa Pirozzi, Annalisa Di Domenico, Annachiara De Luca, Enza Lonardo. LAMC2: New player in stemness and tumor progression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-038.