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Role of hypernutrition and metabolic stress in non-alcoholic steatohepatitis (NASH) driven hepatocellular carcinoma (HCC)

Award Number: P01CA281819
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Role of hypernutrition and metabolic stress in non-alcoholic steatohepatitis (NASH) driven hepatocellular carcinoma (HCC) - PROJECT SUMMARY – OVERALL Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a rising cause of cancer mortality. HCC related to metabolic stress is on the rise, with nonalcoholic steatohepatitis (NASH) rapidly becoming the dominant etiology. We hypothesize that stress-induced metabolic reprogramming via NRF2 and ATF6 alters, glucose, lipid, and cholesterol metabolism to augment glycolysis and induce mitochondrial dysfunction through STARD1 and SAB, which collaborates with genetic alterations to accelerate NASH progression to HCC through a self-sustained downward spiral. Interference with key components of this network may suppress HCC progression and can yield novel interceptive strategies. Our preliminary data indicate that interactions between the cytosol and nucleus (AKT;NRF2), the endoplasmic reticulum (ER; ATF6) and mitochondria (STARD1+SAB) contribute synergistically to NASH-driven HCC. Elimination of any of these components attenuates HCC and their activation exacerbates HCC progression in murine models. Together, our outstanding team of investigators will address the pathological significance and mechanisms underlying the crosstalk between these pathways via 3 projects: Project 1 will interrogate how the newly discovered NRF2- FBP1 tug-of-war is regulated to support HCC progression. It will identify the first cells in which NRF2 and AKT are activated to drive FBP1 degradation and the cues that trigger this switch. Lineage tracing will determine whether NRF2-high HCC directly originates from FBP1-high senescent NASH hepatocytes and the role of diet- induced DNA damage in hepatocyte senescence and mutagenesis will be elucidated. Project 2 will define how ATF6 drives HCC in response to metabolic stress. It will uncover the mechanism by which ER stress and the unfolded protein response transducer ATF6 promotes NASH progression to HCC, likely through NRF2 and FBP1 degradation, the reprogramming of lipid and cholesterol metabolism, and will test whether and how ATF6 ablation or inhibition abrogate NASH-driven HCC. Project 3 will explore how metabolic stress and cholesterol trigger mitochondrial dysfunction through STARD1 and SAB to drive HCC. Mitochondrial outer membrane proteins STARD1 and SAB may contribute to NASH and HCC development through altered cholesterol trafficking and bile acid synthesis, mitochondrial dysfunction that triggers ROS production, resulting in NRF2 and ATF6 activating oxidative and/or ER stress. This PPG offers an unprecedented opportunity for advanced understanding of NASH-driven HCC via proximal metabolic regulators and DNA damage controlled by NRF2, ATF6, and STARD1/SAB. Extensive collaborative interactions and coordinated administrative resources (Core A), shared use of dietary and transgenic mouse models, metabolic profiling/flux studies (Core 1) and extensive “omic” and bioinformatic analyses (Core 2) will further enhance collaborations and ensure uniform success throughout all projects. This P01 offers a unique translational opportunity to define how energy rich diets impact regulators that promote NASH progression to HCC, generating new preventive and therapeutic strategies.


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 = $2,272,153 )
2026	2026	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	3	8/11/2026	NON-COMPETING CONTINUATION	$2,272,153
														Subtotal = $2,272,153

Issue Date FY: 2025 ( Subtotal = $2,302,833 )
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	2	9/19/2025	NON-COMPETING CONTINUATION	$2,302,833
														Subtotal = $2,302,833

Issue Date FY: 2024 ( Subtotal = $2,397,277 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cancer Biology Research	000	1	9/9/2024	NEW	$2,397,277
														Subtotal = $2,397,277

Grand Total All Awards = $6,972,263

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Role of hypernutrition and metabolic stress in non-alcoholic steatohepatitis (NASH) driven hepatocellular carcinoma (HCC)

Award Number: P01CA281819

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/09/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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