Dietary Influence on Liver Metastasis in Pancreatic Cancer
Abstract
Background: Pancreatic cancer is a lethal disease with a 5-year survival rate of only 8% and is projected to become the second-leading cause of cancer-related deaths in the United States by 2030. A major reason for these poor outcomes is that most patients are diagnosed in late stages when the disease has already spread (metastasized) to distant organs, most frequently the liver. However, it is unclear what factors influence liver metastasis. At the same time, the prevalence of obesity has similarly increased over the past decade. Obesity is often associated with the development of fatty liver disease, where excessive nutrients from the diet are stored into the liver as fat. Obesity-related fatty liver disease affects over 80 million people in the United States, and it is the most common chronic liver disease worldwide. Obesity is a risk factor for pancreatic cancer and it dramatically changes the liver, but it is unknown how this affects the development of liver metastasis in pancreatic cancer patients. Preliminary Finding: We fed laboratory mice high-fat diet, which causes obesity and fatty liver disease (as in humans), and then experimentally induced the formation of liver metastases. Compared to mice on a regular diet, the obese mice had greatly increased growth of tumors in their livers. When the tumors were analyzed molecularly, we found that over a hundred genes were specifically turned on in the obese mice and that they were likely under the control of a few molecular switches called transcription factors. This showed that obesity changes what genes are active within the cancer cells. In addition, we looked at the liver cells that neighbor the tumors. In the obese liver only, these cells turned on an enzyme that breaks down fat, suggesting that obesity also changes how liver cells that are close to the tumors make use of nutrients. Hypothesis: Based on these findings, we hypothesize that in the presence of obesity and fatty liver disease, pancreatic cancer cells are more likely to metastasize to the liver because surrounding liver cells break down fat to send signals that turn on genes in the cancer cells that help them grow. Research Plan: To test our hypothesis, we propose two related but independent lines of research. First, focusing on the cancer cells, we will determine specifically how high-fat diet affects the way genes are turned on. We will apply the latest technologies that allow for analysis of gene activity at the level of single cells. These results will build a clear picture of how diet influences the behavior of each tumor cell, and tell us which transcription factors are the most important control switches. We will then block these transcription factors using genetic tools and drugs to confirm that they are responsible for the diet-related molecular changes and faster tumor growth. Second, focusing on the tumor-neighboring liver cells, we will determine how high-fat diet affects the activity of their genes and the metabolic molecules they produce. To do so, we will use a method that labels specifically the liver cells adjacent to the tumor, isolate the labeled cells, and use advanced technologies to measure their gene and metabolic activity. We will then apply genetic tools and drugs to block fat breakdown and exchange between the liver cells and cancer cells, in order to test if that will impair tumor growth. In both lines of research, we will look for the identified transcription factors and fat metabolism genes in samples from obese vs. non-obese patients, which will help us prioritize the genes with highest relevance to humans to test experimentally in the mice. Impact: Our study specifically addresses an increasingly relevant population of pancreatic cancer patients, with potential implications to other metastatic cancers in the setting of obesity and fatty liver disease. We will generate unique datasets that will be of high value to the research community for u
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210911
Entities
People
- Scott W. Lowe
Organizations
- Sloan-Kettering Institute
- United States Army