Abstract 1411: LAMC2 promotes progression and gemcitabine resistance through modulation of EMT and ATP-binding transporters in pancreatic ductal adenocarcinoma

Abstract

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor prognosis. Gemcitabine-based therapeutic options remain the first treatment choice for the majority of PDAC patients. Unfortunately, however, currently there is lack of availability of robust prognostic and predictive biomarkers in patients with PDAC. Laminin γ2 (LAMC2) is frequently overexpressed in several cancers, and its high expression facilitates cancer development and chemoresistance. The role of LAMC2 in disease pathogenesis, as well as its clinical significance, if any, in PDAC remains unclear. Considering that a better understanding of its molecular function will likely help improve the prognosis in PDAC patients, herein, we undertook this study to elucidate the clinical and biological function of LAMC2 in PDAC. Methods: LAMC2 expression was assessed in tissue specimens from a cohort of 114 PDAC patients who received surgical treatment. This was followed by examining the clinical significance of this gene in multiple patient cohorts. The qRT-PCR based gene expression data were subsequently analyzed in the context of prognosis of PDAC patients. Finally, functional characterization of the role of LAMC2 in PDAC was investigated in a series of experiments following small interfering RNA (siRNA)- based knockdown of this gene in pancreatic cancer (PC) cells. Results: Higher expression of LAMC2 significantly correlated with poor survival in PDAC patient cohort (overall survival [OS]: 23.0 vs 14.2 months, Hazard ratio [HR]=1.61; 95% confidence interval [CI], 1.09-2.79, P < 0.01, relapse-free survival [RFS]: 9.0 vs 6.2 months, HR=1.61, 95%CI, 0.96-2.71, P < 0.05). In multivariate analysis which included several clinical factors, elevated LAMC2 expression served as an independent prognostic factor for OS (HR=1.71; 95% CI, 1.09-2.68). Moreover, higher LAMC2 expression levels predicted response to gemcitabine-based adjuvant therapy in patients with PDAC (HR=1.66, 95%CI, 0.94-2.93). The inhibition of LAMC2 expression enhanced gemcitabine sensitivity and induction of apoptosis in PC cell lines. Moreover, siRNA mediated suppression of LAMC2 expression led to inhibited colony formation ability, migration and invasion potential. Furthermore, LAMC2 was found to regulate the expression of various epithelial-mesenchymal transition (EMT) associated genes. In addition, LAMC2 expression significantly correlated with genes associated with the several key ATP-binding cassette (ABC) transporters in both PC cell lines and PDAC tissues. Conclusion: We conclude that LAMC2 regulates gemcitabine sensitivity through EMT and ABC transporter pathways in PDAC, and this gene may be a potential therapeutic target in patients with PDAC. Citation Format: Yasuyuki Okada, Satoshi Nishiwada, Naoki Takahashi, Tetsuji Takayama, Ajay Goel. LAMC2 promotes progression and gemcitabine resistance through modulation of EMT and ATP-binding transporters in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1411.