Lysosomal-IP: A Novel Approach to Investigate Metabolic Reprogramming in TFE3-RCC
Abstract
Background: Translocation renal cell carcinoma (TFE3-RCC) is a morphologically and clinically distinct subtype of RCC. These tumors affect both children and young adults. Interestingly, TFE3-RCC represents up to 40% of pediatric and up to 5% of adult renal cell carcinoma. TFE3-associated RCC is caused by chromosome rearrangements that result in oncogenic activation of the transcription factor TFE3. Following its activation, TFE3 localizes in the nucleus, where it activates the expression of lysosomal biogenesis. Lysosomes are important organelles that break down nutrients to provide building blocks for cancer cells. The mechanisms through which TFE3 functions as an oncogene in TFE3-RCC are not completely understood. Additionally, the impact of TFE3 translocations on the function of lysosomes and the metabolic homeostasis in TFE3-RCC is currently unknown, representing a knowledge gap. Furthermore, therapeutic interventions for TFE3-RCC patients are limited, which necessitates the need for novel and durable treatments. The scientific objective of this project is to study the lysosomal metabolism of TFE3-RCC. We will employ an innovative technique to isolate lysosomes from TFE3-RCC cells and determine which metabolic enzymes are altered, compared to normal kidney cells. Investigation of the lysosome-specific metabolism has not been performed in TFE3-RCC and could identify novel cellular pathways involved in TFE3-RCC tumorigenesis. Short-term Impact: In this project we will address a novel hypothesis: TFE3 translocations alter the lysosomal metabolism in TFE3-RCC. We expect this work to have significant impact, by revealing the metabolic enzymes involved in TFE3-RCC tumorigenesis, which could be therapeutically targeted. Long-term Impact: This may lead to completely novel therapeutic strategies for RCC, with the potential to induce a cytotoxic, rather than cytostatic, effect on TFE3-associated tumors. We believe that by understanding how TFE3-RCC cells break down nutrients at the lysosome and use them for their growth, will allow us to identify new approaches for therapeutic interventions, specific to TFE3-RCC. In summary, this work will impact kidney cancer research by: (1) Defining the impact of TFE3 translocation to the nucleus of RCC cells. (2) Determine the mechanism through which TFE3 translocations impact lysosome metabolism. (3) Identifying novel therapeutic approaches to eliminate TFE3-associated RCC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010829
Entities
People
- Charilaos Filippakis
Organizations
- United States Army