Promotion of colorectal cancer by Streptococcus gallolyticus-a novel mechanism.

Streptococcus gallolyticus subsp. gallolyticus (Sgg) is an opportunistic gut pathobiont. It has a longstanding clinical association with colorectal cancer (CRC). We previously demonstrated that Sgg stimulates CRC cell proliferation and promotes tumor growth in mouse models of CRC (Kumar et al., 2017). Recent studies also indicated that Sgg induced an immune-tolerant environment in the mouse colon conductive for tumor development (Zhang et al., 2018). These results provide strong experimental support for Sgg being an active promoter of tumor development. The molecular mechanism underlying Sgg’s tumor promoting activity was unknown. We investigated the effect of Sgg on CRC cells by analyzing mass spectrometry proteomics data. We found that several types of collagen were upregulated in Sgg-treated cells compared to cells cultured in media only. The upregulation was further confirmed by RT-qPCR and Western blot. Transforming growth factor beta (TGFbeta) is a master regulator of the extracellular matrix. Therefore, we examined the effect of Sgg on the TGFbeta signaling pathway. The results showed that Sgg-treated cells had significantly higher level of phosphorylated Smad2. Sgg treatment also induced the expression of TGFbeta target genes. The effects of Sgg on CRC cells were significantly decreased in the presence of inhibitors for TGFbeta signaling. In addition, we observed that Sgg induced similar effects in mouse colon. Together, these results demonstrate that Sgg activates the TGFbeta signaling pathway in vitro and in vivo. Furthermore, we found that activation of TGFbeta by Sgg is mediated by specific Sgg genes. Deletion of these genes abolished the effect of Sgg on CRC cells in vitro and its ability to promote tumor growth in a mouse model of CRC. These results suggest that TGFbeta activation is a mechanism underlying Sgg’s contribution to tumor growth. Next, we tried to determine if these findings are relevant to CRC patients. Examination of tumor tissues from CRC patients revealed that Sgg-positive tumors exhibit significantly enhanced TGFbeta activity compared to Sgg-negative tumors, suggesting that Sgg-positivity correlates with stronger TGFbeta signaling activities in CRC patients. Taken together, our results highlight a previously unrecognized mechanism in which a colonic microbe activates the TGFbeta signaling pathway to promote the development of CRC. Studies to further delineate this novel mechanism are currently under way. Citation Format: John Taylor, Ritesh Kumar, Amir Sarshekeh, Jennifer Davies, Scott Kopetz, Juan Xu, Yi Xu. Promotion of colorectal cancer by Streptococcus gallolyticus—a novel mechanism [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A21.