Colorectal cancer (CRC) is a major health concern with nearly 2-million new cases of CRC diagnosed worldwide in 2019. While surgical resection of the primary tumor offers a cure for some, up to half of patients undergoing colorectal surgery will develop a postoperative recurrence. With a median survival of only 24 months, almost all patients whom develop a postoperative recurrence will die from their disease with current therapies; there is thus an immediate need to develop new strategies to understand and prevent CRC recurrence. Despite increasing evidence that intestinal bacteria plays a major role in the pathogenesis of primary CRC, how gut microbes influence the development of CRC recurrence has never been addressed. To address this gap in knowledge, Benjamin Shogan MD has developed exciting data demonstrating that CRC recurrence is a microbial driven process. For reasons that remain poorly understood, a high-fat Western diet is the major risk factor for the development of both primary and recurrent CRC. He has discovered that when mice fed a high-fat diet undergo intestinal resection (mimicking the surgery patients undergo for CRC cure) collagenase producing organisms, especially Enterococcus faecalis preferentially colonizes the site of reconnection. He has found that E. faecalis can over-activate critical extracellular matrix proteases, including the urokinase(uPA)-plasminogen system, creating an environment abundant in signals (i.e. uPA, MMP9, plasminogen) well-known to promote tumor progression. Strikingly, when CT26 mouse carcinoma cells are present intraluminally at the time of surgery (mimicking exfoliated viable tumor cells that exist in human patients), they can migrate through healing intestinal tissue to develop tumors identical to human CRC recurrence only when mice are fed a high-fat diet and colonized with collagenolytic organisms. Recent in vitro experiments have found that E. faecalis promotes enhanced invasion and migration of CT26 cells, suggesting that at the intersection of CRC recurrence is bacterial induced metastasis of tumor cells through permeable intestinal tissue. In this K08 application, Dr. Shogan creates a career development plan to acquire his long-term goal of becoming a principal investigator examining how modulation of the intestinal microbiome can improve survival outcomes in patients with CRC. With the guidance of his mentors Ralph Weichselbaum MD and Eugene Chang MD, he will test the hypothesis that the perioperative proliferation of collagenolytic organisms by a high-fat diet creates an intestinal microenvironment that promotes the extraluminal migration of cancer cells, driving CRC recurrence. Using in vivo and in vitro approaches, and samples from his human patients, he will explicate the mechanisms by which collagenolytic organisms, via its interaction with the extracellular matrix, drives the transluminal migration of CT26 cells to form extraluminal tumors. Completion of this work will inform the interaction between host-microbe-cancer cells, and force a complete rethinking and development of novel strategies to prevent and treat colorectal cancer.
With little understanding as to its pathogenesis, colorectal cancer recurrence occurs in up to 40% of patients undergoing surgery, and when it does, it is almost universally fatal. This proposal is focused on studying a novel hypothesis in cancer recurrence and defining the role of intestinal microbes to influence cancer cells towards an invasive phenotype promoting tumor formation. These studies will provide transformative insights into the dynamic interaction between host-microbe-cancer that can be leveraged to provide novel interventions and therapeutics to prevent primary cancer and its recurrence.
