Tumor-intrinsic IFNγ signaling and niche adaptation drive early colonization in ovarian cancer metastasis.
14 affiliations
- 1Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
- 2Harold C. Simmons Comprehensive Cancer Center, Dallas, TX, USA.
- 3Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.
- 4Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
- 5Cecil H. And Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX, USA.
- 6Quantitative Biomedical Research Center, Department of Health Data Science & Biostatistics, Peter O'Donnell Jr. School of Public Health, UT Southwestern Medical Center, Dallas, TX, USA.
- 7Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
- 8Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, IN, USA.
- 9Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
- 10Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, TX, USA.
- 11Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
- 12Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA.
- 13Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA. [email protected].
- 14Harold C. Simmons Comprehensive Cancer Center, Dallas, TX, USA. [email protected].
Abstract
The mechanisms enabling disseminating tumor cells to survive and colonize peritoneal niches during ovarian cancer metastasis remain incompletely understood. Here, we present MetTag, a single-cell barcoding and transcriptome profiling approach with time-stamped batch identifiers to resolve temporal dynamics of dissemination. Sequencing of MetTag barcodes reveals enrichment of early-disseminated clones across metastatic sites, and targeted depletion of pioneers diminishes the outgrowth of later arriving cells. MetTag-coupled single-cell RNA sequencing uncovers a distinct interferon-gamma-centric transcriptional trajectory enriched among pioneer clones. CRISPR/Cas9 screening and subsequent interferon-gamma receptor 1 knockout in pioneer cells significantly reduces metastatic burden, highlighting a critical window where active interferon-gamma signaling shapes the post-seeding metastatic niche and outgrowth. Mechanistically, the tumor-intrinsic interferon-gamma response and peritoneal macrophages cooperatively shield disseminating tumor cells from anoikis. Our study defines the temporal clonal architecture of peritoneal metastasis, revealing a first come, first served dissemination principle, where pioneer fitness determines the success of subsequent colonizers.
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BibTeX
@article{aleksandrovic2026tumorintrinsic,
title = {{Tumor-intrinsic IFNγ signaling and niche adaptation drive early colonization in ovarian cancer metastasis.}},
author = {Emilija Aleksandrovic and Shaneann R Fross and Samantha M Golomb and Wei Ma and Xiyu Liu and Zhuo Zhao and Nikitha M Das and Tanner C Reese and Hazel M Borges and Ates Tenekeci and Lei Yu and Jacqueline Lopez and Min Zhao and Zhenyu Zhong and Kevin M Dean and Jayanthi Lea and Lin Xu and M Sharon Stack and Siyuan Zhang},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77222-8},
url = {https://europepmc.org/article/MED/42834039},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Tumor-intrinsic IFNγ signaling and niche adaptation drive early colonization in ovarian cancer metastasis.
AU - Emilija Aleksandrovic
AU - Shaneann R Fross
AU - Samantha M Golomb
AU - Wei Ma
AU - Xiyu Liu
AU - Zhuo Zhao
AU - Nikitha M Das
AU - Tanner C Reese
AU - Hazel M Borges
AU - Ates Tenekeci
AU - Lei Yu
AU - Jacqueline Lopez
AU - Min Zhao
AU - Zhenyu Zhong
AU - Kevin M Dean
AU - Jayanthi Lea
AU - Lin Xu
AU - M Sharon Stack
AU - Siyuan Zhang
PY - 2026
DA - 2026/09/03
JO - Nature communications
DO - 10.1038/s41467-026-77222-8
UR - https://europepmc.org/article/MED/42834039
AB - The mechanisms enabling disseminating tumor cells to survive and colonize peritoneal niches during ovarian cancer metastasis remain incompletely understood. Here, we present MetTag, a single-cell barcoding and transcriptome profiling approach with time-stamped batch identifiers to resolve temporal dynamics of dissemination. Sequencing of MetTag barcodes reveals enrichment of early-disseminated clones across metastatic sites, and targeted depletion of pioneers diminishes the outgrowth of later arriving cells. MetTag-coupled single-cell RNA sequencing uncovers a distinct interferon-gamma-centric transcriptional trajectory enriched among pioneer clones. CRISPR/Cas9 screening and subsequent interferon-gamma receptor 1 knockout in pioneer cells significantly reduces metastatic burden, highlighting a critical window where active interferon-gamma signaling shapes the post-seeding metastatic niche and outgrowth. Mechanistically, the tumor-intrinsic interferon-gamma response and peritoneal macrophages cooperatively shield disseminating tumor cells from anoikis. Our study defines the temporal clonal architecture of peritoneal metastasis, revealing a first come, first served dissemination principle, where pioneer fitness determines the success of subsequent colonizers.
SN - 2041-1723
ER -