GrantP01CA
Project 2 - Fatty Liver Predisposes to Metastasis: Role of Hepatic Stellate Cells
- Activity
- P01
- Institute
- CA
- Fiscal years
- 2020–2024
- Amount counted
- $1,418,116
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Abstract public domain (NIH RePORTER)
Project Summary/Abstract Liver metastasis is a steep obstacle for curative cancer treatment. Several cancers including prostate (PCa), colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC) commonly metastasize to this site. Data shows that liver metastasis is promoted by endocrine signaling from the primary tumor which can transform the liver microenvironment. Nonetheless, this pre-metastatic to post-metastatic niche transformation can also be influenced by therapy and diet. The ketogenic diet (KD) is a high-fat carb-restrictive diet that mimics fasting by making fatty acids the main source of energy and promoting beta hydroxy butyrate (βHB) synthesis (ketosis). KD has been successfully used to aid patients with neurodegenerative diseases. Additionally, it has been proposed to ameliorate different types of cancer by inducing a reverse-Warburg effect and sensitizing cells to checkpoint inhibitors. However, reports show that βHB enables adaptability to nutritional stress in cancer stem cells and is associated with tumor progression and staging of prostate cancer. Nevertheless, βHB is also a reported tumor suppressor being a known HDAC inhibitor and a signaling molecule through the niacin receptor, GPR109a, in colon and breast cancer cells. Understanding that the liver is the main βHB synthesis organ, in this study we aim to elucidate the effects of a ketogenic metabolism affecting the liver premetastatic niche and its paradoxical roles with PCa and CRC in their distinct metabolic reprogramming.
Public health relevance public domain (NIH RePORTER)
Project Narrative: The paradoxical roles of beta hydroxy butyrate in the liver pro-metastatic niche. The proposed research aims to elucidate the role of ketogenesis in the liver microenvironment for a pro-metastatic niche. This study will be applied to prostate and colorectal cancer metastatic models which are incurable once metastasized and will provide new targetable mechanisms to improve patient care. Therefore, this research pertains to the NIH mission to innovate and advance health care strategies.