Role of Lysosomal Transporters in Promoting the Growth of Clear Cell Renal Cell Carcinoma and Other Tumor Types
Abstract
The subject of our proposed research is clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer. The major risk factors of this disease are highly relevant to the military, i.e., smoking and hypertension, which are particularly prevalent among active-duty military and Veterans, and chronic kidney dialysis, which occurs at a threefold higher rate in the Veterans Health Administration population compared to the general public. Our proposed research will examine how malignant ccRCC cells activate signals that allow them to continually grow and divide. One key growth signal in ccRCC comes from a group of proteins called the mTORC1 pathway, and inhibiting this pathway with rapamycin or related drugs can stop the growth of some ccRCC tumors, even in metastatic disease. However, these drugs have many problematic side effects and do not benefit all ccRCC patients. Thus, we seek to understand the mechanism by which the mTORC1 pathway becomes activated in these cancer cells in order to more intelligently target and prevent this process. Recent research has shown that mTORC1 activation occurs at the lysosome, a cellular compartment where nutrients are recycled and stored, and that adequate nutrient levels in the lysosome are necessary for activation to occur. However, it is not known how lysosomal nutrient levels are "sensed" by the mTORC1 pathway, for example, which specific proteins and nutrients are involved. We noticed that the protein PAT1, which is thought to transport certain molecules across the membrane surrounding the lysosome, is present at very high levels in many ccRCC tumors. Here, we propose to study this protein affects lysosomal nutrient levels and mTORC1 pathway activation. To do this, we will develop a new method for isolating lysosomes and measuring their nutrient contents, which could not previously be done in an accurate and comprehensive manner. Because this method will be broadly applicable, we will also use it to study additional lysosomal proteins present at very high levels in ccRCC and other cancer types. The endpoint of our study will be the identification of lysosomal proteins that are necessary for tumor growth in laboratory animals. We expect that our novel methods and discoveries will significantly advance the scientific fields of lysosome biology and the mTORC1 pathway as a whole. Our findings will also be clinically relevant: for example, in the span of 3-5 years, clinicians could begin testing the levels of PAT1 and/or other lysosomal proteins in tumors to identify patients who would benefit from treatment with rapamycin. This research will also provide the basis for the discovery of new anticancer drugs targeting lysosomal proteins that are essential for tumor growth; due to the long process of drug development and regulatory approval, this outcome is likely to take approximately 10 years to achieve. In these ways, our studies will serve to improve therapeutic options against ccRCC, a deadly disease that disproportionately affects military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510230
Entities
People
- David M. Sabatini
Organizations
- United States Army
- Whitehead Institute