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Determining the mechanism of pks+ E.coli-associated carcinogenesis in early onset colorectal cancer.

Award Number: P50CA257881
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Determining the mechanism of pks+ E.coli-associated carcinogenesis in early onset colorectal cancer. - PROJECT SUMMARY Colorectal cancer (CRC) is now the leading cause of cancer deaths in individuals under 50, yet the causes behind this rapid rise in early onset CRC (EOCRC) remain largely unknown. The microbiome has emerged as potential environmental driver, altering the colon microenvironment through inflammatory/tumorigenic signals, or genotoxins that accelerate carcinogenesis, but why these would disproportionately affect younger people remains elusive. Escherichia coli (E.coli) strains carrying the polyketide synthase (pks) island produce the genotoxin colibactin and have been linked to CRC pathogenesis. While pks+ E.coli are found as commensal bacteria, they can become pathogenic in dysbiosis and inflammation, and are enriched in IBD, polyposis, and CRC patients. Colibactin directly alkylates DNA, leading to mutational A-T rich signatures (SBS-pks) detectable by whole genome sequencing (WGS). Since WGS is not routinely used clinically, we developed an approach to identify SBS-pks signatures in a targeted exon capture assay, MSK-IMPACT. We identify in our institutional pan- cancer cohort of 78,905 tumors 149/1845 samples with MSS CRC with >10% mutations attributable to SBS-pks (Gerstberger et al., in submission). We find that SBS-pks+ CRCs are associated with EOCRC, consistent with a recent WGS study (Diaz-Gay et al., Nature, 2025). To mechanistically investigate why pks+ E. coli preferentially induces CRC in the young, we developed a novel patient-derived organoid (PDO)-microbe co-culture model that leverages reversal of epithelial polarity. Three-month co-culture with human CRC PDOs and NC101 pks+ E.coli or its isogenic ∆pks strain selectively induces SBS-pks signatures in pks+ E.coli co-cultured PDOs. We find that pks+ E.coli activate DNA replication and DNA damage repair (DDR) pathways coupled with cell cycle delay in S phase, indicative of replication stress, and induce a phenotypic switch into more proliferative and regenerative intestinal stem cell (ISC) states that are poised for tumorigenesis. Ageing is associated with delayed cell cycle progression, reduced DNA repair proficiency, proliferation, and stem cell fitness. Using young/old PDO co-culture and mouse CRC models with pks+ and ∆pks E. coli, we will test the hypothesis that (1) the young epithelium has greater DDR and ISC plasticity, enabling error prone repair and dynamic colibactin induced entry into ISC states, while in aged epithelia, colibactin injury induces synthetic lethality due to deficient DNA repair and decreased plasticity. Alternatively, (2) young intestinal epithelia may harbor an epigenetic memory of inflammation from emerging environmental stressors, rendering them poised to tumorigenesis upon colibactin injury, which we will test through epigenomic and inflammatory stimulus-response assays of our existing biobank of young/old normal colon/CRC organoids from patients with/without CRC. Outcomes of this research will inform our understanding of EOCRC mechanisms and have potential implications for exposures and preventative screening.


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: 2025 ( Subtotal = $2,610,565 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	003	4	9/17/2025	SUPPLEMENT FOR EXPANSION	$176,000
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	002	4	8/19/2025	NON-COMPETING CONTINUATION	$2,434,565
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	000	3	12/10/2024	NON-COMPETING CONTINUATION	$0
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	001	3	5/29/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,610,565

Issue Date FY: 2024 ( Subtotal = $2,281,895 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	003	3	9/9/2024	NON-COMPETING CONTINUATION	$0
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	002	3	8/14/2024	NON-COMPETING CONTINUATION	$2,281,895
2024	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	000	2	11/9/2023	NON-COMPETING CONTINUATION	$0
2024	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	001	2	2/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,281,895

Issue Date FY: 2023 ( Subtotal = $2,336,129 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	001	2	8/17/2023	NON-COMPETING CONTINUATION	$44,250
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	000	2	8/15/2023	NON-COMPETING CONTINUATION	$2,291,879
														Subtotal = $2,336,129

Issue Date FY: 2022 ( Subtotal = $2,329,651 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	000	1	9/20/2022	NEW	$2,279,963
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Centers Support Grants	001	1	9/21/2022	NEW	$49,688
														Subtotal = $2,329,651

Grand Total All Awards = $9,558,240

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Determining the mechanism of pks+ E.coli-associated carcinogenesis in early onset colorectal cancer.

Award Number: P50CA257881

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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