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A novel protective role of PYDC5 in colorectal cancer

Award Number: R01CA301129
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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A novel protective role of PYDC5 in colorectal cancer - Summary: Colorectal cancer is the second most deadly cancer in the US. Known risk factors for developing colorectal cancer are genetic mutations as well as environmental triggers and inflammation. While systemic inflammation is a marker for poor prognosis, local inflammation with immune cell infiltration can be associated with a better prognosis in colorectal cancer. Therefore, a better understanding of the readiness of the immune system to locally fight against emerging cancer cells determines colorectal cancer occurrence and progression and compelling evidence supports that modification and priming of the tumor immune microenvironment is an emerging and efficient strategy for the development of novel colorectal cancer therapies. We recently discovered PYDC5, which functions as an inhibitor for the dsDNA-induced AIM2 inflammasome. We now discovered that PYDC5 is expressed in a rare intestinal macrophage population, but that expression is cancer stage-dependently significantly reduced in colorectal cancer patients compared to matched controls. Conversely, macrophage-specific expression of PYDC5 in mice strongly protects from induced and spontaneous colorectal cancer, suggesting that impaired PYDC5 expression skews intestinal homeostasis and promotes colon tumorigenesis. Our preliminary data further imply that an inflammasome-independent, but type I interferon dependent mechanism is involved and that PYDC5 assembles into a novel nuclear signaling complex to promote a unique type I interferon signature to shape the intestinal immune cell and microbiome composition. The research proposed in this MPI application will elucidate the functional consequences from PYDC5 expression on intestinal homeostasis and colorectal cancer in induced and spontaneous models of colorectal cancer, will define the underlying molecular mechanisms by which PYDC5 shapes the tumor immune microenvironment to protect from colorectal cancer, and will functionally define the rare PYDC5+ intestinal macrophage cell population. Collectively, we expect that our research will uncover novel protective molecular mechanisms and expand our knowledge on type I interferon signaling, which can be exploited for the development of novel therapies that positively impact the quality of life of colorectal cancer patients.


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 = $679,353 )
2026	2026	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	1	5/4/2026	NEW	$679,353
														Subtotal = $679,353

Grand Total All Awards = $679,353

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A novel protective role of PYDC5 in colorectal cancer

Award Number: R01CA301129

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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