Colorectal cancer (CRC) is the second cause of cancer-related mortality. Many patients treated with adjuvant chemotherapy present with distant recurrence and resistance to treatment. Better understanding factors influencing patient relapse and metastasis formation upon adjuvant chemotherapy is an important unmet clinical need. In this project, we aim at deciphering the systemic effect of chemotherapy-induced injuries of non-tumoral tissues and their impact on metastatic relapse and treatment responses of colorectal tumors.

We used in vivo mouse model of colorectal cancer liver metastasis. To determine the systemic effect of chemotherapy, we performed untargeted metabolomic analysis of liver, intestine, portal, and systemic serum of mice receiving either a clinically relevant cycle of FOLFOX (5-FU, Oxaliplatin) or control treatment, at day five when cytotoxic drugs were eliminated from the organism and the intestine was in the regenerative phase. We characterized the liver metastasis microenvironment using highly multiplex imaging and flow cytometry.

Pretreatment of mice with FOLFOX durably prevented liver metastasis formation, even when cells were implanted after drug clearance. Such chemotherapy memory effect was gut microbiome-dependent. Portal serum derived from FOLFOX pre-treated mice reduced human CRC tumoroids growth, indicating release of circulating factors. FOLFOX treatment modified the metabolomes of the portal and systemic serum. We identified a microbial derived metabolite which limited growth of human CRC tumoroids in vitro and CRC liver metastasis in mice. Current work focuses on determining the impact of chemotherapy on gut microbiome and the cell-autonomous and microenvironmental mechanisms of the metastasis inhibition by gut-derived bacterial products.

Chemotherapy drastically and durably modified the metabolomes of blood, and these changes were sufficient to confer a prolonged antitumoral protection independently of the direct cytotoxic effect on cancer cells. Our goal is to identify new therapeutic agents that could be used as potentiate existing cancer therapies.