TY  - JOUR
AU  - Erice, Oihane
AU  - Narayanan, Shruthi
AU  - Feliu, Iker
AU  - Entrialgo-Cadierno, Rodrigo
AU  - Malinova, Antonia
AU  - Vicentini, Caterina
AU  - Guruceaga, Elizabeth
AU  - Delfino, Pietro
AU  - Trajkovic-Arsic, Marija
AU  - Moreno, Haritz
AU  - Valencia, Karmele
AU  - Blanco, Ester
AU  - Macaya, Irati
AU  - Öhlund, Daniel
AU  - Khatri, Purvesh
AU  - Lecanda, Fernando
AU  - Scarpa, Aldo
AU  - Siveke, Jens
AU  - Corbo, Vincenzo
AU  - Ponz-Sarvise, Mariano
AU  - Vicent, Silvestre
TI  - Lamc2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth.
JO  - Clinical cancer research
VL  - 29
IS  - 6
SN  - 1078-0432
CY  - Philadelphia, Pa. [u.a.]
PB  - AACR
M1  - DKFZ-2023-00040
SP  - 1137-1154
PY  - 2023
N1  - 2023 Mar 14;29(6):1137-1154
AB  - The identification of 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 queried for human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated.LAMC2 was 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. A LAMC2-regulated network was featured in PDAC including 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 MEK1/2 inhibitors that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids.LAMC2 is a molecular target in PDAC which regulates a transcriptional network that unveils a dual drug combination for cancer treatment.
LB  - PUB:(DE-HGF)16
C6  - pmid:36607777
DO  - DOI:10.1158/1078-0432.CCR-22-0794
UR  - https://inrepo02.dkfz.de/record/186671
ER  -