Wednesday, September 17, 2025 9/17/2025

Identifying the Cellular and Molecular Targets of JAK/STAT-Driven Adipose Wasting to Reverse Cancer Cachexia

Award Number: R01CA266900
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/22/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Identifying the Cellular and Molecular Targets of JAK/STAT-Driven Adipose Wasting to Reverse Cancer Cachexia - ABSTRACT/NARRATIVE Cancer cachexia (CCX), wasting of muscle and/or adipose, is associated with 20-30% of all cancer related deaths.1 Our clinical studies have shown that the presence of CCX is associated with a 50% decrease in median survival (14 months vs 28 months, p<0.001) independent of tumor-directed therapies.2-3 There are no FDA- approved CCX regimens, with a majority of trials focused on limiting sarcopenia. Using multiple established murine CCX mouse models, we consistently observed significant adipose tissue loss compared to muscle atrophy. Furthermore, blocking adipocyte lipolysis using global lipase null mice limited both adipose wasting and sarcopenia in murine models of CCX. Understanding upstream mechanisms cancers use to provoke adipose lipolysis and wasting could offer novel therapeutic targets to reverse CCX syndrome. The complex intracellular (stromal, vascular, immune, and adipocyte) interactions within adipose tissue ultimately regulate CCX wasting by altering the relative signals of adipocyte triglyceride lipolysis and synthesis. To understand the convergence of these interactions, we developed an in vitro CCX adipocyte assay to screen secreted factors from CCX lines that increase adipose inflammation and wasting by inducing adipocyte lipolysis and identified the cytokine leukemia inhibitory factor (LIF).5 Through the JAK-dependent inflammatory reprogramming of adipose tissue in mice, recombinant LIF caused a decrease in adipose mass by >50%, lean mass, and body weight by >10%, recapitulating CCX. LIF also altered the adipose expression and systemic levels of other cyto/adipokines to amplify this inflammation and alter food intake. Use of JAK inhibitors in murine CCX models led to decreased adipose inflammation (decreased STAT3 phosphorylation), adipocyte lipolysis, and adipose/muscle wasting, all increasing survival. To understand the contributions of adipose intracellular signaling in the regulation of CCX adipose inflammation, we selectively silenced the LIF receptor (LIFR) or STAT3 in adipocytes. Both mouse models doubled their adipose mass compared to littermate controls during development highlighting an inverse CCX phenotype. When allotransplanted with CCX tumors, both models still demonstrated adipose inflammation with persistent STAT3 phosphorylation, resulting in a partial suppression of CCX and defining the non-adipocyte cellular contributions of adipose to CCX wasting. FACS analysis verified longitudinal enrichment of immune cells during CCX progression, offering additional tumor/cytokine targets supporting CCX adipose inflammation and wasting. We hypothesize that CCX adipose inflammation occurs via a JAK-dependent Tumor-Cytokine-Adipose Axis that reprograms adipose through JAK/STAT signaling of multiple cellular subtypes to increase adipocyte lipolysis and alter secretion of cyto/adipokines, resulting in wasting. SA1-2 will dissect the multiple cellular/molecular signaling components of this axis facilitating adipose inflammation in support of this CCX wasting. SA3 will validate associations between JAK/STAT signaling events in human adipose to CCX induction in 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: 2025 ( Subtotal = $1,232,409 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	002	4	9/3/2025	SUPPLEMENT FOR EXPANSION	$198,888
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	001	4	8/27/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,033,521
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	000	3	8/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,232,409

Issue Date FY: 2024 ( Subtotal = $699,508 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	001	3	8/22/2024	SUPPLEMENT FOR EXPANSION	$198,888
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	000	3	8/21/2024	NON-COMPETING CONTINUATION	$500,620
														Subtotal = $699,508

Issue Date FY: 2023 ( Subtotal = $528,437 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	000	2	8/28/2023	NON-COMPETING CONTINUATION	$528,437
														Subtotal = $528,437

Issue Date FY: 2022 ( Subtotal = $539,221 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Treatment Research	000	1	9/22/2022	NEW	$539,221
														Subtotal = $539,221

Grand Total All Awards = $2,999,575

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Identifying the Cellular and Molecular Targets of JAK/STAT-Driven Adipose Wasting to Reverse Cancer Cachexia

Award Number: R01CA266900

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/22/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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