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Dissecting Differentiation and Immune Niches in Liposarcoma for Therapeutic Discovery

Award Number: K08CA308868
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/14/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Dissecting Differentiation and Immune Niches in Liposarcoma for Therapeutic Discovery - Sarcomas are rare connective tissue cancers associated with dysfunctional mesenchymal differentiation. Half of all patients diagnosed with sarcoma will develop metastatic disease, where outcomes are poor and have not improved over the last 40 years. There is a critical need to understand the underlying molecular drivers of sarcoma cell state that result in disease progression to develop novel therapeutic strategies. Liposarcoma (LPS) is among the most common sarcomas and an informative model to study aberrant differentiation, given its well-differentiated (WDLPS) and dedifferentiated (DDLPS) subtypes. Despite shared genomic alterations, these subtypes differ dramatically in morphology, clinical behavior, and outcome. DDLPS has high metastatic potential, a six-fold increased risk of death, and limited treatment options. To investigate the mechanisms of LPS dedifferentiation, I led a multiomic analysis of patient-derived WDLPS and DDLPS tumors, revealing that DDLPS tumor cells lack expression of the adipogenic transcription factor PPARG2 and are epigenetically poised for GLP1-mediated differentiation. I also discovered subtype-specific immune microenvironments, whereby DDLPS is enriched for type I interferon signaling and immunosuppressive macrophages and WDLPS for TNF-alpha and lipid-associated macrophages. These findings uncovered a previously unrecognized intersection between metabolism, differentiation, and immune regulation in sarcoma. This proposal integrates experimental and computational approaches to test the overarching hypothesis that metabolic regulators (PPARG2, GLP1) and tumor–macrophage interactions govern sarcoma differentiation and metastasis. These studies provide critical mechanistic validation of hypotheses generated from patient-derived multiomic analyses. Aim 1 will define how PPARG2 restoration affects DDLPS differentiation and metastatic potential in vitro and in vivo. Vertebrate animal models are essential to determine whether molecular programs identified in patient-derived tumors causally regulate metastatic progression in vivo, providing functional validation that cannot be achieved in vitro. Aim 2 will determine how GLP1 signaling reprograms LPS cell state through noncanonical pathways and evaluate its effects on differentiation and metastatic progression. Aim 3 will identify LPS subtype-specific macrophage niches and identify targetable receptors promoting immune evasion. This work will yield foundational insights into cell state regulation and immune crosstalk in sarcoma, to ultimately guide the development of differentiation-based and immunologic therapeutic strategies. As an Instructor in Sarcoma at Dana-Farber Cancer Institute and Harvard Medical School, I am uniquely positioned to bridge computational discovery with mechanistic experimentation. My career development plan focuses on gaining expertise at the interface of tumor immunology, macrophage biology, and advanced computational analysis of tumor–immune crosstalk in human tissues under the mentorship of Drs. Eliezer Van Allen and Suzanne George. This focused training will enable me to translate multidimensional patient-derived data into testable biological hypotheses and therapeutic strategies. The integrated clinical, genomic, and translational infrastructure of DFCI and HMS provides the ideal environment for my transition to independence as a physician-scientist dedicated to defining metabolic and immune regulators of sarcoma differentiation.


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 = $288,006 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	1	9/14/2026	NEW	$288,006
														Subtotal = $288,006

Grand Total All Awards = $288,006

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Dissecting Differentiation and Immune Niches in Liposarcoma for Therapeutic Discovery

Award Number: K08CA308868

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/14/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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