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

Active Project Grant Awarded Last action

Award ID
P01CA281819
Recipient
Awarding agency
Obligated
$6,972,263

Award facts

Assistance listing
93.396 Cancer Biology Research
Completion date 43% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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.

Transactions

Action Obligated Date
Amendment $2,272,153
Amendment $2,302,833
Original award $2,397,277

Subawards

Subrecipient Amount Awarded
University Of Southern California We will be participating in a P01 application as Project 3. The focus is on NASH induced HCC using the MUP-uPa model of chronic ER stress fed a high fat, high… $487,772
University Of California, San Diego Core 2 will deploy powerful targeted data-analysis techniques, including genomics and transcriptomics analysis and methods for identifying the landscape of… $284,959
University Of California, San Diego Project 1 directed by Dr. Michael Karin at UCSD is focused on the study of NRF2as key metabolic regulator that controls the development and malignant… $457,045
University Of Southern California We will be participating in a P01 application as Project 3. The focus is on NASH induced HCC using the MUP-uPa model of chronic ER stress fed a high fat, high… $328,265
Fundacio De Recerca Clinic Barcelona-Institut D’investigacions Biomediques August Pi I Sunyer Project 3 focuses on the contribution of two mitochondria proteins, Sab and StARD1, which increase in NASH and further increase in HCC and alter mitochondria… $161,141
University Of California, San Diego Core 2 will deploy powerful targeted data-analysis techniques, including genomics and transcriptomics analysis and methods for identifying the landscape of… $285,913

Quick answers

Who received award P01CA281819?

P01CA281819 was awarded to Sanford Burnham Prebys Medical Discovery Institute by National Cancer Institute (National Institutes of Health) on September 9, 2024.

How much is award P01CA281819 worth?

$6,972,263 has been obligated on P01CA281819.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login