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Investigation into the regulation of mitochondrial dynamics, intra-organelle communication, and metabolic reprogramming by the PKA-fusion oncoprotein

Award Number: K99CA307323
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/03/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Investigation into the regulation of mitochondrial dynamics, intra-organelle communication, and metabolic reprogramming by the PKA-fusion oncoprotein - Project Summary Fibrolamellar carcinoma (FLC) is a rare and aggressive liver cancer predominantly affecting adolescents and young adults, with limited effective treatments for advanced stages. Nearly all FLC tumors harbor the unique DNAJB1-PRKACA fusion gene (PKAfus) and show abnormal mitochondrial accumulation. Major challenges include understanding how PKAfus promotes tumor growth and identifying targetable therapeutic vulnerabilities, complicated by a lack of relevant models. To fill this gap, I have developed novel patient-derived FLC models, including the first and only FLC permanent patient-derived FLC cell line, and engineered systems expressing PKAfus. My recent findings reveal that PKAfus-driven growth involves phosphorylation and inactivation of salt- inducible kinases (SIKs), triggering transcriptional changes via CRTC2 activation and p300-mediated acetylation, thus facilitating malignant cell proliferation. This data highlights a crucial oncogenic mechanism of PKAfus and suggests potential targeting of CRTC2/p300 in treating FLC, while prompting further questions for understanding FLC biology and enhancing therapeutic strategies. I plan to explore the cellular processes regulated by the PKAfus-SIK axis. My primary scientific goal, as part of this NIH Pathway to Independence, is to explore how the PKA-SIK-CRTC2 axis influences mitochondrial and organelles remodeling and metabolic rewiring needed by cancer cells. I hypothesize that PKAfus promotes tumorigenesis by altering mitochondrial and lysosomal functions, disrupting cellular balance to facilitate malignant growth. I propose an integrative approach using advanced metabolomics, spatial imaging, and in vivo studies. My research focuses on three specific aims: (1) Understanding how PKAfus disrupts mitochondrial dynamics; (2) Examining the impact of mitochondrial dysfunction on lysosomal function and stress responses in FLC; (3) Identifying metabolic vulnerabilities from these disruptions and assessing therapeutic strategies. The Bardeesy and Mostoslavsky laboratories at Massachusetts General Hospital Cancer Center offer an ideal setting for my research, focusing on cancer metabolism and signaling pathways. During the K99 phase, I will receive crucial training in organelle imaging, metabolism, and in vivo metabolic flux studies essential for my independent research career. The K99/R00 Pathway to Independence Award will help me establish a multidisciplinary program on organelle dysfunction and metabolic rewiring in cancer, advancing targeted therapies for FLC and tumors linked to mitochondrial and lysosomal changes.


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 = $161,676 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cancer Research Manpower	000	1	9/3/2026	NEW	$161,676
														Subtotal = $161,676

Grand Total All Awards = $161,676

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Investigation into the regulation of mitochondrial dynamics, intra-organelle communication, and metabolic reprogramming by the PKA-fusion oncoprotein

Award Number: K99CA307323

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/03/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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