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Mechanism and functional consequences of dietary lipids in lineage specification and tumor growth in oncohistone gliomas

Award Number: U01CA286537
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Mechanism and functional consequences of dietary lipids in lineage specification and tumor growth in oncohistone gliomas - PROJECT SUMMARY: Mechanism and functional consequences of dietary lipids in lineage specification and tumor growth in oncohistone gliomas Diffuse midline gliomas (DMGs) are the most aggressive brain tumors of childhood. Malignant growth of H3K27M DMGs is linked to reduced activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) and diminished H3K27 trimethylation (H3K27me3), a repressive chromatin mark. H3K27M-induced reconfiguration of chromatin architecture suppresses differentiation of cycling glial progenitor cells in the developing brain. This is further accompanied by increased PDGFRA signaling supporting the expansion of these progenitor cells. Nevertheless, the tumor cells retain some latent differentiation potential. We and others have shown that this potential can be unmasked by treatment with serum or pharmacologic remodeling of chromatin, which drive differentiation of these tumor cells to more mature glial cell lineages and reduce their tumorigenic potential. In preliminary studies, we have found that; (i) diet-derived lipids in the form of n3-polyunsaturated fatty acids (n3- PUFAs) are required for serum-induced differentiation of H3K27 DMGs, and (ii) n3-PUFAs’ effect in this setting is associated with increased H3K27me3 marks, enrichment of more differentiated glial cell population, and reduction of cycling glial progenitor cell population. This suggests a previously unappreciated link between these dietary lipids and epigenetic modulation of cell lineage specification. Against this backdrop, our central hypothesis is that the PUFA pathway (specifically n3-PUFA) modulates cell fate decisions and epigenetic programs relevant for H3K27M-mediated gliomagenesis. We test this hypothesis by addressing three fundamental questions. First, what is the functional role of n3-PUFAs in self-renewal and lineage-specific differentiation of H3K27M glial progenitors? Aim 1 addresses this question by interrogating the causal link between n3-PUFAs and H3K27M glioma cell state specification through a combination of loss- and gain-of- function, nutrient rescue assays, and single-cell transcriptomic to rigorously examine the functional contribution of these lipids to cell fate. Second, what is the biochemical mechanism whereby n3-PUFAs influence these cell states? Aim 2 addresses this question by characterizing a mechanistic links between these lipids and the H3K27M DMG chromatin landscape by examining chromatin accessibility of loci specific for distinct cell lineage, and by interrogating PRC2 activity and PDGFRA signaling as biochemical targets of n3-PUFAs. Third, do PUFA enrichment strategies have therapeutic potential in DMGs? Aim 3 addresses this question by testing the anti- tumor effects of n3-PUFA diets or genetic activation of the PUFA pathway in H3K27M DMG PDX models. These studies are aligned with PAR-23-051 in that they test n3-PUFAs as dietary variables that mechanistically link epigenetic modifiers/programs to H3K27M DMG cell fate decisions and tumorigenic potential.


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 = $702,458 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	3	4/13/2026	NON-COMPETING CONTINUATION	$702,458
2026	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	2/9/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $702,458

Issue Date FY: 2025 ( Subtotal = $702,459 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	3/4/2025	NON-COMPETING CONTINUATION	$632,213
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$70,246
														Subtotal = $702,459

Issue Date FY: 2024 ( Subtotal = $721,959 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	3/12/2024	NEW	$721,959
														Subtotal = $721,959

Grand Total All Awards = $2,126,876

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Mechanism and functional consequences of dietary lipids in lineage specification and tumor growth in oncohistone gliomas

Award Number: U01CA286537

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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