Leptin receptor deficiency suppresses gastric tumorigenesis by limiting stromal activation and tumor microenvironment development.

Abstract

Leptin receptor (LEPR) signaling has been implicated in multiple malignancies; however, its role in gastric tumors remains poorly defined. We previously demonstrated that mice with gastrointestinal epithelial cell-specific deletion of suppressor of cytokine signaling 3 (SOCS3 cKO), a negative feedback regulator of LEPR signaling, develop gastric tumors due to aberrant leptin production and LEPR activation. Here, we demonstrate that concurrent deletion of both Socs3 and Lepr (double knockout; DKO) under the same promoter substantially suppresses gastric tumorigenesis and markedly prolonged survival. Whereas SOCS3 cKO mice exhibited early stromal activation, increased TGF-{beta}1 production, accumulation of cancer-associated fibroblasts (CAFs) and collagen deposition, these tumor-promoting alterations were substantially attenuated in DKO mice. Additionally, DKO mice showed reduced inflammatory cytokine and chemokine signaling, decreased the accumulation of Gr-1+CD11b+ myeloid-derived suppressor cells, and reduced LEPR and TGF-{beta} signaling. Analysis of The Cancer Genome Atlas stomach adenocarcinoma cohort revealed high LEPR expression in the chromosomal instability and genomically stable subtypes, correlating with poor prognosis. Moreover, LEPR expression was mutually exclusive with CLDN18 and ERBB2, two major therapeutic biomarkers, and positively correlated with a CAF-related transcriptional signature. Our findings identify LEPR signaling in epithelial cells as a key driver of gastric tumorigenesis through promotion of stromal activation and tumor microenvironment development. They further highlight LEPR as a promising therapeutic target for patients with gastric cancer who are unlikely to benefit from current ERBB2/HER2- or CLDN18-directed therapies.