التفاصيل البيبلوغرافية
| العنوان: |
Ongoing genome doubling promotes evolvability and immune dysregulation in ovarian cancer. |
| المؤلفون: |
McPherson A, Vázquez-García I, Myers MA, Zatzman M, Al-Rawi D, Weiner A, Freeman S, Mohibullah N, Satas G, Williams MJ, Ceglia N, Zhang AW, Li J, Lim JLP, Wu M, Choi S, Havasov E, Grewal D, Shi H, Kim M, Schwarz R, Kaufmann T, Dinh KN, Uhlitz F, Tran J, Wu Y, Patel R, Ramakrishnan S, Kim D, Clarke J, Green H, Ali E, DiBona M, Varice N, Kundra R, Broach V, Gardner GJ, Roche KL, Sonoda Y, Zivanovic O, Kim SH, Grisham RN, Liu YL, Viale A, Rusk N, Lakhman Y, Ellenson LH, Tavaré S, Aparicio S, Chi DS, Aghajanian C, Abu-Rustum NR, Friedman CF, Zamarin D, Weigelt B, Bakhoum SF, Shah SP |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 15. Date of Electronic Publication: 2024 Jul 15. |
| نوع المنشور: |
Journal Article; Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
Whole-genome doubling (WGD) is a critical driver of tumor development and is linked to drug resistance and metastasis in solid malignancies. Here, we demonstrate that WGD is an ongoing mutational process in tumor evolution. Using single-cell whole-genome sequencing, we measured and modeled how WGD events are distributed across cellular populations within tumors and associated WGD dynamics with properties of genome diversification and phenotypic consequences of innate immunity. We studied WGD evolution in 65 high-grade serous ovarian cancer (HGSOC) tissue samples from 40 patients, yielding 29,481 tumor cell genomes. We found near-ubiquitous evidence of WGD as an ongoing mutational process promoting cell-cell diversity, high rates of chromosomal missegregation, and consequent micronucleation. Using a novel mutation-based WGD timing method, doubleTime , we delineated specific modes by which WGD can drive tumor evolution: (i) unitary evolutionary origin followed by significant diversification, (ii) independent WGD events on a pre-existing background of copy number diversity, and (iii) evolutionarily late clonal expansions of WGD populations. Additionally, through integrated single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signaling and cGAS-STING pathway activation result from ongoing chromosomal instability and are restricted to tumors that remain predominantly diploid. This contrasted with predominantly WGD tumors, which exhibited significant quiescent and immunosuppressive phenotypic states. Together, these findings establish WGD as an evolutionarily 'active' mutational process that promotes evolvability and dysregulated immunity in late stage ovarian cancer. |
| تواريخ الأحداث: |
Date Created: 20240729 Latest Revision: 20240729 |
| رمز التحديث: |
20240729 |
| مُعرف محوري في PubMed: |
PMC11275742 |
| DOI: |
10.1101/2024.07.11.602772 |
| PMID: |
39071261 |
| قاعدة البيانات: |
MEDLINE |
Full Text Finder