Obesity and high-fat diets are serious risk factors for intestinal cancers. The most rapidly-dividing cells in the human body reside in the intestine and rely on the proper functioning of actively dividing progenitor cells, such as intestinal stem cells (ISCs), to sustain it. Derangement of the signals that control the growth of ISCs causes cancer. Although fatty molecules, called lipids, are known to control the growth ISCs, the mechanisms by which specific lipids affect cancer development are not well understood. Lipid synthesis is controlled by a family of genes called sterol regulatory element-binding proteins (SREBPs). SREBP-2 makes cholesterol. My recent work has shown that SREBP-2 has...

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Obesity and high-fat diets are serious risk factors for intestinal cancers. The most rapidly-dividing cells in the human body reside in the intestine and rely on the proper functioning of actively dividing progenitor cells, such as intestinal stem cells (ISCs), to sustain it. Derangement of the signals that control the growth of ISCs causes cancer. Although fatty molecules, called lipids, are known to control the growth ISCs, the mechanisms by which specific lipids affect cancer development are not well understood. Lipid synthesis is controlled by a family of genes called sterol regulatory element-binding proteins (SREBPs). SREBP-2 makes cholesterol. My recent work has shown that SREBP-2 has a critical role in sustaining growth of the intestine. I have found that depriving the intestine of dietary cholesterol forces it to make its own cholesterol by using SREBP-2. When the intestine makes its own cholesterol, it also produces a number of lipid by-products. I propose that these lipid by-products stimulate intestinal tumor formation. In agreement with this proposal, I have found that blocking SREBP-2 prevents the formation of these lipid by-products and prevents the formation of intestinal tumors in mice. Therefore, in this project I plan to study, in much greater detail, the role of SREBP-2 in intestinal tumorigenesis. The expected outcome of the experiments in this grant proposal is the identification of new ways by which lipids control the formation of intestinal tumors, particularly colorectal cancer. This outcome will have a positive impact on human health because it is feasible that these newly-identified lipid tumor signals will represent drug targets for the treatment of colon cancer, which is the 3rd most common cause of cancer death in the U.S. and an emerging health threat in Texas given the recent, very concerning increase in colon cancer in younger populations.

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