Related Experiment Video

Updated: Aug 28, 2025

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
10:27

Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts

Published on: July 25, 2020

7.4K

Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer

Abhinav Achreja1,2,3,4, Tao Yu5, Anjali Mittal1,3,6

  • 1Laboratory for Systems Biology of Human Diseases, University of Michigan, Ann Arbor, MI, USA.

Nature Metabolism
|September 21, 2022
PubMed

Insights

Researchers identified a new method to find collateral lethal genes, revealing MTHFD2 as a target in ovarian tumors with UQCR11 deletions. Inhibiting MTHFD2 led to complete tumor remission, offering a promising new cancer therapy.

Area of Science:

  • Oncology
  • Metabolic Engineering
  • Genomics

Background:

  • Tumour suppressor gene deletions can co-occur with essential gene loss, creating dependencies on functional paralogues.
  • Identifying these collateral lethal genes is crucial for developing targeted cancer therapies, but no methodology currently exists.

Purpose of the Study:

  • To develop a novel framework for identifying collateral lethal genes using metabolic fluxes.
  • To uncover MTHFD2 as a collateral lethal gene in ovarian tumours with UQCR11 deletions.

Main Methods:

  • Developed the Collateral Lethal Gene Identification via Metabolic fluxes (CLIM) framework.
  • Utilized machine learning and genome-scale metabolic flux analysis.
  • Validated findings through in vivo experiments and MTHFD2 inhibition.

Main Results:

  • Identified MTHFD2 as a collateral lethal gene in UQCR11-deleted ovarian tumours.
  • Demonstrated MTHFD2's non-canonical oxidative function in providing mitochondrial NAD+.
  • Confirmed that MTHFD2 inhibition leads to complete remission of UQCR11-deleted ovarian tumours in vivo.

Conclusions:

  • The CLIM framework effectively identifies collateral lethal genes.
  • Targeting MTHFD2 shows broad efficacy in UQCR11-deleted ovarian cancers, regardless of genetic background or tumour stroma.
  • This discovery presents a promising new therapeutic strategy for ovarian cancer.

More Related Videos

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer09:08

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer

Published on: January 12, 2020

6.8K
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

2.8K

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
7.8K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Lethal Alleles02:41

Lethal Alleles

Agouti: A Lethal Allele
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
15.7K
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...
3.9K
Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
14.9K