Targeting Lysosomal Biogenesis in Renal Tumors with TSC1/2 Loss
Abstract
The MiT/TFE family of transcription factors include the proteins TFEB and TFE3. These transcription factors are particularly important in renal carcinoma because they are involved in genetic rearrangements leading to their overexpression in "translocation renal cell carcinomas." However, we know very little about whether these transcription factors are important in other types of renal cell carcinoma, nor do we understand why they are oncogenic (causing cancer or leading to its progression). Understanding the answer to these questions may enable us to target the activity of the MiT/TFEs and to design new therapies for some subsets of renal cell carcinoma. One well-known function of MiT/TFE transcription factors is their role in increasing the number and function of an intracellular organelle called the lysosome. The lysosome is basically a bag of digestive enzymes within cells where proteins or cell parts that are no longer needed are sent to be degraded and recycled to make new proteins. The function of lysosomes is likely particularly important in cancer cells since tumor cells frequently outgrow their blood supply and must grow in low-nutrient conditions. The ability to "recycle" non-essential proteins and cell parts in the lysosome enables cancer cells to survive without many nutrients. Thus, having more lysosomes (due to more MiT/TFE proteins and more activity of these proteins) may help cancer cells to survive. We recently studied what controls the levels and activity of MiT/TFE genes in normal cells. We found that a signaling pathway called mTORC1 signaling leads to increased levels of MiT/TFE genes and increased lysosomal biogenesis when it is continuously active. This is particularly interesting because many non-clear cell renal cell carcinomas have highly activated mTORC1 signaling, which is most commonly due to loss of the tuberous sclerosis (TSC1/2) tumor suppressors. Thus, activating mTORC1 signaling may be an alternative pathway--similar to genetic rearrangements of TFEB and TFE3--for renal cell carcinomas to increase TFEB and TFE3 expression, increase lysosomal activity, and survive and grow. Consistent with this, non-clear cell renal cell carcinomas with continuously active mTORC1 signaling (due to TSC1/2 loss) resemble translocation renal cell carcinomas pathologically and both overexpress lysosomal proteins, which is what helps pathologists to recognize them and distinguish them from other tumor types. If increased levels of MiT/TFEs and lysosome formation are common characteristics of renal tumors with TSC1/2 loss and renal translocation carcinomas, then this suggests a potentially new and targeted therapy that could be effective in both tumor types: inhibition of the lysosome. Lysosome inhibitors have been tested in renal cell carcinoma patients and have few toxic side-effects, however, to date we have not had access to very potent lysosomal inhibitors. Now, however, chemists have designed a new generation of lysosomal inhibitors that are far more potent. In addition, these new drugs, called dimeric quinacrines, have the added benefit of simultaneously suppressing mTORC1 signaling. In this proposal, we would like to: * Test whether mouse or human renal tumors with TSC1/2 loss (and continuous mTORC1 signaling) resemble renal translocation carcinomas in terms of increased TFEB and TFE3 levels with increased lysosome formation and activity. * Test whether TFEB or TFE3 expression is required for tumor formation or tumor growth in mouse renal tumors with TSC1/2 loss. * Test whether dimeric quinacrine lysosomal inhibitors are effective in reducing tumor formation or tumor growth in mouse models of renal tumors with TSC1/2 loss or translocation renal cell carcinoma. Innovation: We will be the first to test whether there are important similarities between non-clear cell renal cell carcinomas with TSC1/2 loss and translocation renal cell carcinomas and whether these tumor type
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010843
Entities
People
- Tamara L Lotan
Organizations
- Johns Hopkins University
- United States Army