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Evaluating the role of the tumor macroenvironment in cancer cachexia

Award Number: F99CA305566
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 07/30/2027

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Evaluating the role of the tumor macroenvironment in cancer cachexia - Project Summary Cancer cachexia is a severe metabolic syndrome characterized by muscle and adipose wasting. It is a significant complication faced by cancer patients that reduces quality of life, limits treatment efficacy, and accounts for nearly a third of a third of cancer-associated deaths. Despite its prevalence, cancer cachexia remains untreatable by current conventional means, as its complex multi-organ etiology is poorly understood. Cachexia involves dysregulated crosstalk between the tumor, the tumor microenvironment (TMiE), and organs essential for energy homeostasis including muscle, adipose, the liver, and the brain. Thus, examination of the broader tumor macroenviornment (TMaE) is critical. Using pancreatic cancer as a model system, this proposal aims to elucidate the mechanisms by which cancer cells and the TMiE coordinate with the TMaE to drive cachexia, thereby identifying novel therapeutic targets for intervention. In the F99 phase, I will investigate the tumor-TMiE interaction focusing on how tumor-associated macrophages (TAMs) contribute to muscle and adipose wasting. I have shown that TAMs potentiate muscle atrophy via tumor necrosis factor weak inducer of apoptosis (TWEAK) signaling 1 . My current investigation suggests pancreatic cancer cells recruit and instruct TAMs to secrete a well-known metabolic regulator, known as Growth and Differentiation Factor 15 (GDF15), which acts on the hindbrain receptor GFRAL to accelerate cachexia. Specifically, this is carried out via a cancer cell-derived Colony Stimulating Factor 1 (CSF1 )-dependent mechanism. Genetic manipulation of both CSF1 and GDF15 successfully modulated cachexia phenotypes in our models. These findings suggest that targeting TAM-mediated signaling pathways can mitigate cachexia. The proposed experiments in the F99 phase will assess this therapeutic opportunity. In the KOO phase, I will expand the focus to liver-mediated pathways in cachexia. Like the nervous system, the liver plays a central role in systemic energy homeostasis. During the early phases of cancer progression, tumor-secreted factors prime the liver for metastasis. I will address whether early established metastatic priming events can drive the onset of cancer cachexia. This aim will utilize advanced animal models and metabolic assays to assess liver dysfunction as an early driver of cachexia. This work will provide a multi-organ perspective on cancer cachexia, unveiling the complex signaling network involving tumor cells tumor, the TMiE, and the TMaE. The insights from this research will not only enhance our understanding of cancer cachexia etiology but also identify potential targets for intervention, ultimately improving the survival and quality of life of 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 = $43,234 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Research Manpower	000	2	7/20/2026	NON-COMPETING CONTINUATION	$43,234
														Subtotal = $43,234

Issue Date FY: 2025 ( Subtotal = $44,158 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Research Manpower	000	1	7/29/2025	NEW	$44,158
														Subtotal = $44,158

Grand Total All Awards = $87,392

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Evaluating the role of the tumor macroenvironment in cancer cachexia

Award Number: F99CA305566

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 07/30/2027

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