PROJECT SUMMARY / ABSTRACT
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.
