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Modulation of the tumor microenvironment by Fusobacterium nucleatum and co-infecting microbes in colorectal cancer

Award Number: R01CA293361
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Modulation of the tumor microenvironment by Fusobacterium nucleatum and co-infecting microbes in colorectal cancer - PROJECT SUMMARY/ABSTRACT Fusobacterium nucleatum (Fn), a bacterium typically found in the human oral cavity and a rare member of the lower gastrointestinal tract microbiota in healthy individuals, is significantly enriched in human colorectal cancer (CRC) tissues. Extensive epidemiological studies have established a strong association between high Fn levels within CRC tumors and disease recurrence, metastasis, and poor patient prognosis. However, Fn does not exist alone within these tumors; it coexists with a specific group of anaerobic bacterial species. Our previous work demonstrated the persistence of both Fn and these co-infecting bacteria in distant metastases of CRC patients and in CRC patient-derived xenografts (PDXs). Additionally, antibiotic treatment of PDXs effectively reduced intratumoral microbial load and slowed tumor growth, emphasizing the integral role of Fn and co-infecting bacterial communities within the CRC tumor microenvironment (TME). Despite these findings, the field of cancer microbiome research has predominantly focused on bulk tissue molecular analysis, resulting in a fundamental gap in our understanding of the spatial and cellular interactions between Fn, co-infecting bacteria, and human components within the TME. Recent discoveries by my team have revealed that Fn and co-infecting bacteria exhibit a heterogeneous distribution within human CRC tumors, localized to distinct tumor niches. These infected regions are characterized by myeloid cell infiltration, upregulation of immune checkpoint proteins PD1 and CTLA4, and reduced T-cell infiltration. Our central hypothesis posits that Fn and specific co-infecting bacteria collectively reshape their infected CRC tumor niche by influencing cancer epithelial cell functions and the spatial distribution of immune cells in infected regions; ultimately driving cancer progression. To test this hypothesis, we will leverage cutting-edge spatial omics techniques to investigate how the composition, load, and spatial distribution of Fn and co-infecting bacteria affect the function and spatial organization of host cellular components within the TME of both human and murine CRC tumors (Aim 1). Furthermore, we will dissect host-bacterial interactions at the single-cell level to reveal specific host cell types susceptible to invasion by Fn and co-infecting bacteria within the CRC TME and determine how these intracellular bacteria alter host signaling pathways at the single-cell level (Aim 2). My team has the breadth of experience to accomplish this project as it relates to the multiomics nature of analyses for Fn, co-infecting bacteria, and host interactions within the CRC TME. Successful completion of this proposal will bridge a critical knowledge gap in our understanding of how Fn and co-infecting bacteria shape their infected niche and influence cancer cell behavior in both primary and metastatic CRC. This research holds the potential to reveal novel therapeutic targets for inhibiting Fn-associated CRC progression or enhancing existing CRC treatments. While our primary focus is on CRC, the host-microbiota mechanistic insights gained from this study are likely to have broader implications for infection-associated cancers.


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 = $660,541 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	4/2/2026	NEW	$660,541
														Subtotal = $660,541

Grand Total All Awards = $660,541

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Modulation of the tumor microenvironment by Fusobacterium nucleatum and co-infecting microbes in colorectal cancer

Award Number: R01CA293361

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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