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Nociceptive control of bladder tumorigenesis

Award Number: R01CA312146
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/26/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Nociceptive control of bladder tumorigenesis - Despite recent advances in the treatment of malignant diseases, bladder cancer continues to represent a significant unmet clinical need. Nociceptors - sensory neurons that trigger the sensation of pain or itch in response to noxious stimuli - can affect immune response in various contexts; however, their role in the pathobiology of bladder cancer remains unexplored. Preliminary work for this project employing an orthotopic mouse model of non-muscle invasive bladder cancer (NMIBC) revealed that bladder tumors are densely innervated by nociceptors. Furthermore, pharmacologic nociceptor ablation or chemogenetic inhibition of nociceptor electrical activity resulted in immune-mediated tumor rejection. Pilot studies examining cocultures of monocytes and dorsal root ganglion-derived nociceptors indicate that nociceptors rapidly induce monocyte differentiation into immunosuppressive myeloid-derived suppressor cells (MDSCs). Accordingly, monocyte-derived MDSCs were the first immune cells to populate incipient bladder cancer lesions and represented the most abundant immune cell type in advanced tumor-bearing urinary bladders. Collectively, these preliminary findings suggest that NMIBC may exploit an immunosuppressive neuro-immune axis to evade anti-tumor immune responses and identify nociceptive nerve fibers as potential targets for the treatment or prevention of bladder cancer. To test this hypothesis, Aim 1 will build on these initial observations to fully explore the effect of nociceptors on primary urinary bladder carcinomas and metastatic disease. Aim 2 will define the molecular mechanisms and consequences of the three-way communication between bladder tumor cells, nociceptive fibers, and immune cells. The proposed research plan will rigorously dissect a complex multi-step process involving dynamic interactions between malignant cancer cells, nociceptors, monocytes, and T cells that occur in a highly time-dependent manner within the tumor and the surrounding bladder tissue, as well as in draining lymph nodes and in the blood circulation. To accomplish this research, the use of live mice is essential because there are currently no in vitro or in silico alternatives that could accurately recapitulate this complex multi-system process in its entirety. In aggregate, the proposed work will dissect the role of nociceptors in the pathogenesis of NMIBC, identify the immune cells within the tumor microenvironment that are controled by nociceptors, and determine the molecular means of nociceptor-immune cell communication. Thus, given the high unmet need for better therapies for bladder cancer, this work is highly significant.


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 = $688,893 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	6/26/2026	NEW	$688,893
														Subtotal = $688,893

Grand Total All Awards = $688,893

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Nociceptive control of bladder tumorigenesis

Award Number: R01CA312146

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/26/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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