IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37147-y.html
   My bibliography  Save this article

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

Author

Listed:
  • Shigekazu Murakami

    (Georgetown University Medical Center)

  • Shannon M. White

    (Georgetown University Medical Center)

  • Alec T. McIntosh

    (Georgetown University Medical Center)

  • Chan D. K. Nguyen

    (Georgetown University Medical Center)

  • Chunling Yi

    (Georgetown University Medical Center)

Abstract

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.

Suggested Citation

  • Shigekazu Murakami & Shannon M. White & Alec T. McIntosh & Chan D. K. Nguyen & Chunling Yi, 2023. "Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37147-y
    DOI: 10.1038/s41467-023-37147-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37147-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-37147-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Bieke Decaesteker & Geertrui Denecker & Christophe Van Neste & Emmy M. Dolman & Wouter Van Loocke & Moritz Gartlgruber & Carolina Nunes & Fanny De Vloed & Pauline Depuydt & Karen Verboom & Dries Romba, 2018. "TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    2. Ye Chen & Liang Xu & Anand Mayakonda & Mo-Li Huang & Deepika Kanojia & Tuan Zea Tan & Pushkar Dakle & Ruby Yu-Tong Lin & Xin-Yu Ke & Jonathan W. Said & Jianxiang Chen & Sigal Gery & Ling-Wen Ding & Ya, 2019. "Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    3. Sapna Puri & Nilotpal Roy & Holger A. Russ & Laura Leonhardt & Esra K. French & Ritu Roy & Henrik Bengtsson & Donald K. Scott & Andrew F. Stewart & Matthias Hebrok, 2018. "Replication confers β cell immaturity," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    4. Neil Vasan & José Baselga & David M. Hyman, 2019. "A view on drug resistance in cancer," Nature, Nature, vol. 575(7782), pages 299-309, November.
    5. Timothy Bailey & Pawel Krajewski & Istvan Ladunga & Celine Lefebvre & Qunhua Li & Tao Liu & Pedro Madrigal & Cenny Taslim & Jie Zhang, 2013. "Practical Guidelines for the Comprehensive Analysis of ChIP-seq Data," PLOS Computational Biology, Public Library of Science, vol. 9(11), pages 1-8, November.
    6. Raymond G. Fox & Nikki K. Lytle & Dawn V. Jaquish & Frederick D. Park & Takahiro Ito & Jeevisha Bajaj & Claire S. Koechlein & Bryan Zimdahl & Masato Yano & Janel L. Kopp & Marcie Kritzik & Jason K. Si, 2016. "Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma," Nature, Nature, vol. 534(7607), pages 407-411, June.
    7. Peter Bailey & David K. Chang & Katia Nones & Amber L. Johns & Ann-Marie Patch & Marie-Claude Gingras & David K. Miller & Angelika N. Christ & Tim J. C. Bruxner & Michael C. Quinn & Craig Nourse & L. , 2016. "Genomic analyses identify molecular subtypes of pancreatic cancer," Nature, Nature, vol. 531(7592), pages 47-52, March.
    8. Adrian Vallejo & Naiara Perurena & Elisabet Guruceaga & Pawel K. Mazur & Susana Martinez-Canarias & Carolina Zandueta & Karmele Valencia & Andrea Arricibita & Dana Gwinn & Leanne C. Sayles & Chen-Hua , 2017. "An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Irati Macaya & Marta Roman & Connor Welch & Rodrigo Entrialgo-Cadierno & Marina Salmon & Alba Santos & Iker Feliu & Joanna Kovalski & Ines Lopez & Maria Rodriguez-Remirez & Sara Palomino-Echeverria & , 2023. "Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Bieke Decaesteker & Amber Louwagie & Siebe Loontiens & Fanny De Vloed & Sarah-Lee Bekaert & Juliette Roels & Suzanne Vanhauwaert & Sara De Brouwer & Ellen Sanders & Alla Berezovskaya & Geertrui Deneck, 2023. "SOX11 regulates SWI/SNF complex components as member of the adrenergic neuroblastoma core regulatory circuitry," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Wei Xu & Sau Har Lee & Fengjun Qiu & Li Zhou & Xiaoling Wang & Tingjie Ye & Xudong Hu, 2021. "Association of SMAD4 loss with drug resistance in clinical cancer patients: A systematic meta-analysis," PLOS ONE, Public Library of Science, vol. 16(5), pages 1-14, May.
    5. Bárbara Andrade Barbosa & Saskia D. Asten & Ji Won Oh & Arantza Farina-Sarasqueta & Joanne Verheij & Frederike Dijk & Hanneke W. M. Laarhoven & Bauke Ylstra & Juan J. Garcia Vallejo & Mark A. Wiel & Y, 2021. "Bayesian log-normal deconvolution for enhanced in silico microdissection of bulk gene expression data," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    6. Xiaoting Sun & Wenhai Sui & Zepeng Mu & Sisi Xie & Jinxiu Deng & Sen Li & Takahiro Seki & Jieyu Wu & Xu Jing & Xingkang He & Yangang Wang & Xiaokun Li & Yunlong Yang & Ping Huang & Minghua Ge & Yihai , 2023. "Mirabegron displays anticancer effects by globally browning adipose tissues," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. James T. Topham & Erica S. Tsang & Joanna M. Karasinska & Andrew Metcalfe & Hassan Ali & Steve E. Kalloger & Veronika Csizmok & Laura M. Williamson & Emma Titmuss & Karina Nielsen & Gian Luca Negri & , 2022. "Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    8. Jonathan J. Swietlik & Stefanie Bärthel & Chiara Falcomatà & Diana Fink & Ankit Sinha & Jingyuan Cheng & Stefan Ebner & Peter Landgraf & Daniela C. Dieterich & Henrik Daub & Dieter Saur & Felix Meissn, 2023. "Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    9. Gregor Werba & Daniel Weissinger & Emily A. Kawaler & Ende Zhao & Despoina Kalfakakou & Surajit Dhara & Lidong Wang & Heather B. Lim & Grace Oh & Xiaohong Jing & Nina Beri & Lauren Khanna & Tamas Gond, 2023. "Single-cell RNA sequencing reveals the effects of chemotherapy on human pancreatic adenocarcinoma and its tumor microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    10. Pedro Madrigal & Siwei Deng & Yuliang Feng & Stefania Militi & Kim Jee Goh & Reshma Nibhani & Rodrigo Grandy & Anna Osnato & Daniel Ortmann & Stephanie Brown & Siim Pauklin, 2023. "Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    11. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Renata Bordeira-Carriço & Joana Teixeira & Marta Duque & Mafalda Galhardo & Diogo Ribeiro & Rafael D. Acemel & Panos. N. Firbas & Juan J. Tena & Ana Eufrásio & Joana Marques & Fábio J. Ferreira & Telm, 2022. "Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    13. S. Randriamanantsoa & A. Papargyriou & H. C. Maurer & K. Peschke & M. Schuster & G. Zecchin & K. Steiger & R. Öllinger & D. Saur & C. Scheel & R. Rad & E. Hannezo & M. Reichert & A. R. Bausch, 2022. "Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    14. Yalan Deng & Xianghou Xia & Yang Zhao & Zilong Zhao & Consuelo Martinez & Wenjuan Yin & Jun Yao & Qinglei Hang & Weiche Wu & Jie Zhang & Yang Yu & Weiya Xia & Fan Yao & Di Zhao & Yutong Sun & Haoqiang, 2021. "Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    15. Marie-Eve Wedge & Victoria A. Jennings & Mathieu J. F. Crupi & Joanna Poutou & Taylor Jamieson & Adrian Pelin & Giuseppe Pugliese & Christiano Tanese Souza & Julia Petryk & Brian J. Laight & Meaghan B, 2022. "Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    16. Meilin Xue & Youwei Zhu & Yongsheng Jiang & Lijie Han & Minmin Shi & Rui Su & Liwen Wang & Cheng Xiong & Chaofu Wang & Ting Wang & Shijie Deng & Dong Wu & Yizhi Cao & Lei Dong & Fan Bai & Shulin Zhao , 2023. "Schwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    17. Hongjuan Yao & Wenping Song & Rui Cao & Cheng Ye & Li Zhang & Hebing Chen & Junting Wang & Yuchen Shi & Rui Li & Yi Li & Xiujun Liu & Xiaofei Zhou & Rongguang Shao & Liang Li, 2022. "An EGFR/HER2-targeted conjugate sensitizes gemcitabine-sensitive and resistant pancreatic cancer through different SMAD4-mediated mechanisms," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    18. Yanfen Zheng & Xingyang Li & Shuang Deng & Hongzhe Zhao & Ying Ye & Shaoping Zhang & Xudong Huang & Ruihong Bai & Lisha Zhuang & Quanbo Zhou & Mei Li & Jiachun Su & Rui Li & Xiaoqiong Bao & Lingxing Z, 2023. "CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    19. Liang-Yu Fu & Tao Zhu & Xinkai Zhou & Ranran Yu & Zhaohui He & Peijing Zhang & Zhigui Wu & Ming Chen & Kerstin Kaufmann & Dijun Chen, 2022. "ChIP-Hub provides an integrative platform for exploring plant regulome," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Peter Bailey & Rachel A. Ridgway & Patrizia Cammareri & Mairi Treanor-Taylor & Ulla-Maja Bailey & Christina Schoenherr & Max Bone & Daniel Schreyer & Karin Purdie & Jason Thomson & William Rickaby & R, 2023. "Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37147-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.