Abstract PO-089: Identification of a LAMC2-regulated network featuring targetable effectors for dual therapies in pancreatic cancer
Authors: Narayanan Shruthi , Erice Oihane , Feliu Iker , Vicentini Caterina , Entrialgo-Cadierno Rodrigo , Valencia Karmele , Guruceaga Elisabet , Khatri Purvesh , Corbo Vicenzo , Cambra Silvestre Vicent , Ponz-Sarvise Mariano 
Published: November 2021

Abstract
Background: Pancreatic cancer stands as one of the deadliest tumors, in part due to the limited efficacy of currently existing therapies. Pancreatic cancer is characterized at the genomic level by the almost universal presence of KRAS mutations. Phenotypically, it features an incipient desmoplastic stroma with a protein component formed by collagens, 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. While a role for LAMC2 in migration and invasion has been previously described, little is known about a potential function in cell proliferation and viability. Moreover, LAMC2 inhibition has been shown to enhance the activity of conventional chemotherapeutic agents. However, whether its abrogation can increase the effect of targeted therapies is yet to be defined. Finally, the direct relationship between LAMC2 and the KRAS oncogene network is yet to be defined. Methods: A meta-analysis of several human PDAC data sets 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 (KrasLSLG12D, 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. Cellular and molecular analysis were deployed to dissect the mechanism of action of LAMC2 in PDAC. A dual pharmacological combination based on LAMC2-regulated effectors was also tested in human and mouse pancreatic cancer models. Results: At the clinical level, we observed that LAMC2 is overexpressed in human PDAC patients with regard to normal tissue. 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 was driven by an induction in apoptosis and a decrease in S phase consistent across species. Mechanistically, LAMC2 was linked to the KRAS pathway via transcriptional regulation of the transcription factor FOSL1/AP1, which was also a member of the cross-tumors signature. Furthermore, LAMC2 controlled a gene signature that overlaps with KRAS- and FOSL1-regulated gene signatures, which was also highly expressed in various pancreatic cancer data sets, and includes the targetable kinase AXL. Lastly, concomitant pharmacological inhibition of AXL and the FOSL1 upstream regulator MEK1/2 displayed a more adverse effect on human and pancreatic pancreatic cancer than each single drug alone. Conclusion: These data suggest that LAMC2 is a molecular target tightly linked to KRAS oncogene signaling that regulates downstream effectors amenable to the development of combination therapies.
Citation Format: Shruthi Narayanan, Oihane Erice, Iker Feliu, Caterina Vicentini, Rodrigo Entrialgo-Cadierno, Karmele Valencia, Elisabet Guruceaga, Purvesh Khatri, Vicenzo Corbo, Silvestre Vicent Cambra, Mariano Ponz-Sarvise. Identification of a LAMC2-regulated network featuring targetable effectors for dual therapies 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-089.