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Elucidating the role and mechanisms by which collagenase producing intestinal bacteria promote colorectal cancer recurrence and metastasis following surgery.

Award Number: K08CA248957
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Elucidating the role and mechanisms by which collagenase producing intestinal bacteria promote colorectal cancer recurrence and metastasis following surgery. - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	THE UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	5	2/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $241,693 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	001	5	2/13/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	5	12/11/2024	NON-COMPETING CONTINUATION	$241,693
														Subtotal = $241,693

Issue Date FY: 2024 ( Subtotal = $241,693 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	4	1/2/2024	NON-COMPETING CONTINUATION	$241,693
														Subtotal = $241,693

Issue Date FY: 2023 ( Subtotal = $241,703 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	3	12/23/2022	NON-COMPETING CONTINUATION	$241,703
														Subtotal = $241,703

Issue Date FY: 2022 ( Subtotal = $241,703 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	2	1/6/2022	NON-COMPETING CONTINUATION	$241,703
														Subtotal = $241,703

Issue Date FY: 2021 ( Subtotal = $241,703 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	1	12/18/2020	NEW	$241,703
														Subtotal = $241,703

Grand Total All Awards = $1,208,495

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Elucidating the role and mechanisms by which collagenase producing intestinal bacteria promote colorectal cancer recurrence and metastasis following surgery.

Award Number: K08CA248957

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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