Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome–associated MSH2-deficient endometrial cancer

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway changes. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based on 2 mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared with non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.

Authors

Institutions

Publication Details

Journal
JCI Insight
Published
2025-02-18
DOI
https://doi.org/10.1172/jci.insight.185946
Citations
6
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
8.83

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome–associated MSH2-deficient endometrial cancer

Melinda S. Yates, Collene Jeter, Malgorzata Anna Zal, Deena M. Scoville et al.
6 citations
JCI Insight
Genetic factors in colorectal cancer
8.83
article

Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome–associated MSH2-deficient endometrial cancer

Melinda S. Yates, Collene Jeter, Malgorzata Anna Zal, Deena M. Scoville, Elizabeth M. Whitley, Hyun-Eui Kim, Rosemarie Schmandt, Brenda Melendez, Lin Tan, Russell R. Broaddus, Philip L. Lorenzi, Richard K. Yang, Joseph Celestino, Kenneth Dunner, Leah Peralta, Mikayla B. Bowen, Tae‐Hoon Kim, Qian Zhang, Jae‐Wook Jeong, Nisha Gokul, Karen Lu, WaiKin Chan, Diana Moreno
article en
6 citations

Abstract

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway changes. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based on 2 mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared with non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.

JCI InsightVol. 10(6)
University of North Carolina at Chapel Hill (US), The University of Texas MD Anderson Cancer Center (US), University of Missouri Health System (US), Institute of Bioinformatics (IN), The University of Texas Health Science Center (US), University of Missouri (US), The University of Texas Health Science Center at Houston (US)
Foundation for Women's Cancer, Cancer Prevention and Research Institute of Texas, Baylor University, National Institutes of Health, University of Texas MD Anderson Cancer Center, Gillings School of Public Health, National Cancer Institute
Openalex Percentile: Top 2%
Genetic factors in colorectal cancer
8.83
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.