Academic Journal
Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas
العنوان: | Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas |
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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 |
DOI: | 10.1038/s41467-023-37147-y |
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