Academic Journal

Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas

التفاصيل البيبلوغرافية
العنوان: Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas
المؤلفون: Murakami, Shigekazu, White, Shannon M., McIntosh, Alec T., Nguyen, Chan D. K., Yi, Chunling
المساهمون: U.S. Department of Health & Human Services | NIH | National Cancer Institute, National Science Foundation
المصدر: Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723
بيانات النشر: Springer Science and Business Media LLC
سنة النشر: 2023
الوصف: Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Here, by employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.
نوع الوثيقة: article in journal/newspaper
اللغة: English
DOI: 10.1038/s41467-023-37147-y
الاتاحة: http://dx.doi.org/10.1038/s41467-023-37147-y
https://www.nature.com/articles/s41467-023-37147-y.pdf
https://www.nature.com/articles/s41467-023-37147-y
Rights: https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0
رقم الانضمام: edsbas.1A2C19A2
قاعدة البيانات: BASE
الوصف
DOI:10.1038/s41467-023-37147-y