Gut Bacterium Morganella morganii-Secreted Proteins Promote Colorectal Tumor Progression through CD137 Upregulation...

The development and progression of Colorectal Cancer (CRC) are closely linked to gut microbiota dysbiosis. However, the pathogenic functions and mechanisms of specific microbiota-derived factors in CRC are not well defined. In this study, we focused on Morganella morganii (M. morganii), a commensal bacterium significantly enriched in the gut of CRC patients, to investigate its potential role in promoting CRC progression.

We first compared the fecal abundance of M. morganii between patients with CRC and healthy controls in a clinical cohort. From its culture supernatant, a high-molecularweight secreted protein mixture, designated M-T3, was purified. In vitro, HCT116 human CRC cells were treated with M-T3 to assess its effects on proliferation, clonogenic potential, and migration. The role of the NF-κB pathway was examined using pharmacological inhibition. In vivo, an HCT116 xenograft mouse model was established, and M-T3 was administered intratumorally. Tumor growth was monitored, and excised tumors were analyzed for expression of CD137 and proliferative activity.

Analysis of a clinical cohort revealed a significant enrichment of M. morganii in fecal samples from CRC patients compared to healthy controls. Mechanistically, treatment with M-T3 activated the NF-κB signaling pathway and consequently was associated with upregulation of CD137 in vitro. M-T3 treatment significantly enhanced the proliferation, clonogenicity, and migration of HCT116 cells, which were effectively reversed by NF-κB pathway inhibition. In vivo, intratumoral delivery of M-T3 accelerated tumor growth in HCT116 xenografts, accompanied by elevated tumor expression of CD137 and an increase in the proliferation marker Ki-67.

This work demonstrates that M. morganii promotes CRC progression via its secreted protein mixture, M-T3, through NF-κB signaling, and is associated with CD137 upregulation in tumor cells. Contrary to the classical view of CD137 as an immune costimulator, its tumor cell-intrinsic expression is associated with malignant phenotypes rather than confirmed functional causality. These findings establish a "bacterial secretome-tumor signaling axis" as a novel mechanism in microbiota-driven carcinogenesis.

Collectively, our work showed that M. morganii promotes colorectal cancer progression via the secreted protein mixture M-T3, which activates the NF-κB signaling pathway and is associated with upregulation of CD137. These findings suggest a potential bacterial secretome-tumor signaling link in CRC. Further studies are required to identify the upstream sensing mechanism of M-T3 and determine the functional contribution of CD137 to M-T3-induced malignant phenotypes.