Related Experiment Video

Updated: May 29, 2025

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
09:58

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

2.7K

Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma

Jiao Li1,2, Kaimeng Huang2,3, Meha Thakur1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Nature Metabolism
|February 6, 2025
PubMed

Insights

Translocation renal cell carcinoma (tRCC) uniquely relies on oxidative phosphorylation (OXPHOS) due to TFE3 gene fusions. Inhibiting EGLN1 exploits this metabolic vulnerability, offering a new therapeutic strategy for tRCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer subtype.
  • TFE3 gene fusions drive tRCC pathogenesis through poorly understood mechanisms.

Purpose of the Study:

  • To elucidate the metabolic reprogramming driven by TFE3 fusions in tRCC.
  • To identify tRCC-specific vulnerabilities associated with its metabolic state.

Main Methods:

  • Genome-scale CRISPR screening.
  • Analysis of metabolic pathways, focusing on oxidative phosphorylation (OXPHOS) and NADH reductive stress.
  • Investigated the role of EGLN1 and HIF-1α.

Main Results:

  • TFE3 fusions rewire tRCCs towards OXPHOS, unlike other renal cancers.
  • tRCCs exhibit vulnerability to NADH reductive stress.
  • EGLN1 was identified as a tRCC-selective vulnerability.
  • EGLN1 inhibition stabilizes HIF-1α, halts tRCC growth, and shifts metabolism away from OXPHOS.

Conclusions:

  • tRCC is dependent on a mitochondria-centered metabolic program driven by TFE3 fusions.
  • EGLN1 inhibition represents a potential therapeutic strategy for OXPHOS-dependent tRCC.

More Related Videos

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer09:40

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer

Published on: August 2, 2024

2.6K
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing09:49

Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing

Published on: July 5, 2019

9.5K

Related Concept Videos

Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
8.7K
The Retinoblastoma Gene01:20

The Retinoblastoma Gene

Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.7K
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.7K
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
7.3K
Metastasis02:30

Metastasis

Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
5.5K