IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34864-8.html
   My bibliography  Save this article

Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas

Author

Listed:
  • Joseph G. Kern

    (Boston University School of Medicine)

  • Andrew M. Tilston-Lunel

    (Boston University School of Medicine)

  • Anthony Federico

    (Boston University School of Medicine
    Boston University)

  • Boting Ning

    (Boston University School of Medicine
    Boston University)

  • Amy Mueller

    (Boston University School of Medicine
    Boston University)

  • Grace B. Peppler

    (Boston University School of Medicine)

  • Eleni Stampouloglou

    (Boston University School of Medicine)

  • Nan Cheng

    (Boston University School of Medicine)

  • Randy L. Johnson

    (MD Anderson Cancer Center)

  • Marc E. Lenburg

    (Boston University School of Medicine
    Boston University)

  • Jennifer E. Beane

    (Boston University School of Medicine
    Boston University)

  • Stefano Monti

    (Boston University School of Medicine
    Boston University
    Boston University School of Public Health)

  • Xaralabos Varelas

    (Boston University School of Medicine)

Abstract

Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of Krt14 and Sox9-expressing basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Gene expression analyses of LATS1/2-deleted mammary epithelial cells notably revealed a transcriptional program that associates with human basal-like breast cancers. Our study demonstrates in vivo roles for the LATS1/2 kinases in mammary epithelial homeostasis and luminal-basal fate control and implicates signaling networks induced upon the loss of LATS1/2 activity in the development of basal-like breast cancer.

Suggested Citation

  • Joseph G. Kern & Andrew M. Tilston-Lunel & Anthony Federico & Boting Ning & Amy Mueller & Grace B. Peppler & Eleni Stampouloglou & Nan Cheng & Randy L. Johnson & Marc E. Lenburg & Jennifer E. Beane & , 2022. "Inactivation of LATS1/2 drives luminal-basal plasticity to initiate basal-like mammary carcinomas," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34864-8
    DOI: 10.1038/s41467-022-34864-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34864-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-022-34864-8?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. Rajshekhar R. Giraddi & Mona Shehata & Mercedes Gallardo & Maria A. Blasco & Benjamin D. Simons & John Stingl, 2015. "Stem and progenitor cell division kinetics during postnatal mouse mammary gland development," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    2. Shany Koren & Linsey Reavie & Joana Pinto Couto & Duvini De Silva & Michael B. Stadler & Tim Roloff & Adrian Britschgi & Tobias Eichlisberger & Hubertus Kohler & Olulanu Aina & Robert D. Cardiff & Moh, 2015. "PIK3CAH1047R induces multipotency and multi-lineage mammary tumours," Nature, Nature, vol. 525(7567), pages 114-118, September.
    3. Shenghong Ma & Zhengming Wu & Feng Yang & Jianmin Zhang & Randy L. Johnson & Michael G. Rosenfeld & Kun-Liang Guan, 2021. "Hippo signalling maintains ER expression and ER+ breast cancer growth," Nature, Nature, vol. 591(7848), pages 1-10, March.
    4. Sirio Dupont & Leonardo Morsut & Mariaceleste Aragona & Elena Enzo & Stefano Giulitti & Michelangelo Cordenonsi & Francesca Zanconato & Jimmy Le Digabel & Mattia Forcato & Silvio Bicciato & Nicola Elv, 2011. "Role of YAP/TAZ in mechanotransduction," Nature, Nature, vol. 474(7350), pages 179-183, June.
    5. Adrian Britschgi & Stephan Duss & Sungeun Kim & Joana Pinto Couto & Heike Brinkhaus & Shany Koren & Duvini De Silva & Kirsten D. Mertz & Daniela Kaup & Zsuzsanna Varga & Hans Voshol & Alexandra Vissie, 2017. "The Hippo kinases LATS1 and 2 control human breast cell fate via crosstalk with ERα," Nature, Nature, vol. 541(7638), pages 541-545, January.
    6. Alexandra Van Keymeulen & Ana Sofia Rocha & Marielle Ousset & Benjamin Beck & Gaëlle Bouvencourt & Jason Rock & Neha Sharma & Sophie Dekoninck & Cédric Blanpain, 2011. "Distinct stem cells contribute to mammary gland development and maintenance," Nature, Nature, vol. 479(7372), pages 189-193, November.
    7. Mel Greaves & Carlo C. Maley, 2012. "Clonal evolution in cancer," Nature, Nature, vol. 481(7381), pages 306-313, January.
    8. Luwei Tao & Dongxi Xiang & Ying Xie & Roderick T. Bronson & Zhe Li, 2017. "Induced p53 loss in mouse luminal cells causes clonal expansion and development of mammary tumours," Nature Communications, Nature, vol. 8(1), pages 1-13, 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. Yael Aylon & Noa Furth & Giuseppe Mallel & Gilgi Friedlander & Nishanth Belugali Nataraj & Meng Dong & Ori Hassin & Rawan Zoabi & Benjamin Cohen & Vanessa Drendel & Tomer Meir Salame & Saptaparna Mukh, 2022. "Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Shenghong Ma & Tracy Tang & Gary Probst & Andrei Konradi & Chunyu Jin & Fulong Li & J. Silvio Gutkind & Xiang-Dong Fu & Kun-Liang Guan, 2022. "Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Song Li & Wenbin Yu & Fei Xie & Haitao Luo & Zhimin Liu & Weiwei Lv & Duanbo Shi & Dexin Yu & Peng Gao & Cheng Chen & Meng Wei & Wenhao Zhou & Jiaqian Wang & Zhikun Zhao & Xin Dai & Qian Xu & Xue Zhan, 2023. "Neoadjuvant therapy with immune checkpoint blockade, antiangiogenesis, and chemotherapy for locally advanced gastric cancer," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Aurore Claude-Taupin & Pierre Isnard & Alessia Bagattin & Nicolas Kuperwasser & Federica Roccio & Biagina Ruscica & Nicolas Goudin & Meriem Garfa-Traoré & Alice Regnier & Lisa Turinsky & Martine Burti, 2023. "The AMPK-Sirtuin 1-YAP axis is regulated by fluid flow intensity and controls autophagy flux in kidney epithelial cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Lichun Ma & Sophia Heinrich & Limin Wang & Friederike L. Keggenhoff & Subreen Khatib & Marshonna Forgues & Michael Kelly & Stephen M. Hewitt & Areeba Saif & Jonathan M. Hernandez & Donna Mabry & Roman, 2022. "Multiregional single-cell dissection of tumor and immune cells reveals stable lock-and-key features in liver cancer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    6. Adam C. Weiner & Marc J. Williams & Hongyu Shi & Ignacio Vázquez-García & Sohrab Salehi & Nicole Rusk & Samuel Aparicio & Sohrab P. Shah & Andrew McPherson, 2024. "Inferring replication timing and proliferation dynamics from single-cell DNA sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    7. Ana Sofia Rocha & Alejandro Collado-Solé & Osvaldo Graña-Castro & Jaime Redondo-Pedraza & Gonzalo Soria-Alcaide & Alex Cordero & Patricia G. Santamaría & Eva González-Suárez, 2023. "Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. Julio Diaz Caballero & Rachel M. Wheatley & Natalia Kapel & Carla López-Causapé & Thomas Van der Schalk & Angus Quinn & Liam P. Shaw & Lois Ogunlana & Claudia Recanatini & Basil Britto Xavier & Leen T, 2023. "Mixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    9. Noushin Niknafs & Violeta Beleva-Guthrie & Daniel Q Naiman & Rachel Karchin, 2015. "SubClonal Hierarchy Inference from Somatic Mutations: Automatic Reconstruction of Cancer Evolutionary Trees from Multi-region Next Generation Sequencing," PLOS Computational Biology, Public Library of Science, vol. 11(10), pages 1-26, October.
    10. María García-García & Sara Sánchez-Perales & Patricia Jarabo & Enrique Calvo & Trevor Huyton & Liran Fu & Sheung Chun Ng & Laura Sotodosos-Alonso & Jesús Vázquez & Sergio Casas-Tintó & Dirk Görlich & , 2022. "Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    11. Albert H Gough & Ning Chen & Tong Ying Shun & Timothy R Lezon & Robert C Boltz & Celeste E Reese & Jacob Wagner & Lawrence A Vernetti & Jennifer R Grandis & Adrian V Lee & Andrew M Stern & Mark E Schu, 2014. "Identifying and Quantifying Heterogeneity in High Content Analysis: Application of Heterogeneity Indices to Drug Discovery," PLOS ONE, Public Library of Science, vol. 9(7), pages 1-16, July.
    12. Saakian, David B. & Vardanyan, Edgar & Yakushkina, Tatiana, 2020. "Evolutionary model with recombination and randomly changing fitness landscape," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 541(C).
    13. Shuangshuang Wan & Kepeng Wang & Peihong Huang & Xian Guo & Wurui Liu & Yaocheng Li & Jingjing Zhang & Zhiyang Li & Jiacheng Song & Wenjing Yang & Xianzheng Zhang & Xianguang Ding & David Tai Leong & , 2024. "Mechanoelectronic stimulation of autologous extracellular vesicle biosynthesis implant for gut microbiota modulation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    14. Kirstin Meyer & Nicholas C. Lammers & Lukasz J. Bugaj & Hernan G. Garcia & Orion D. Weiner, 2023. "Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    15. Zhao Wang & Jan Lauko & Amanda W. Kijas & Elliot P. Gilbert & Petri Turunen & Ramanathan Yegappan & Dongxiu Zou & Jitendra Mata & Alan E. Rowan, 2023. "Snake venom-defined fibrin architecture dictates fibroblast survival and differentiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    16. Christopher R S Banerji & Simone Severini & Carlos Caldas & Andrew E Teschendorff, 2015. "Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer," PLOS Computational Biology, Public Library of Science, vol. 11(3), pages 1-23, March.
    17. Zheng Zhang & Baoyong Sha & Lingzhu Zhao & Huan Zhang & Jinteng Feng & Cheng Zhang & Lin Sun & Meiqing Luo & Bin Gao & Hui Guo & Zheng Wang & Feng Xu & Tian Jian Lu & Guy M. Genin & Min Lin, 2022. "Programmable integrin and N-cadherin adhesive interactions modulate mechanosensing of mesenchymal stem cells by cofilin phosphorylation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    18. Sujin Kang & Jaekyung Kim & Areum Park & Minsoo Koh & Wonji Shin & Gayoung Park & Taeyun A. Lee & Hyung Jin Kim & Heonjong Han & Yongbo Kim & Myung Kyung Choi & Jae Hyung Park & Eunhye Lee & Hyun-Soo , 2023. "TRIM40 is a pathogenic driver of inflammatory bowel disease subverting intestinal barrier integrity," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    19. Maryam Ghaderi Najafabadi & G. Kenneth Gray & Li Ren Kong & Komal Gupta & David Perera & Huw Naylor & Joan S. Brugge & Ashok R. Venkitaraman & Mona Shehata, 2023. "A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Jianyu Ye & Fahong Li & Ting Hua & Kewei Ma & Jinyu Wang & Zixin Zhao & Zhongning Yang & Chen Luo & Ruohan Jia & Yaming Li & Menghan Hao & Jian Wu & Mengji Lu & Zhenghong Yuan & Jiming Zhang & Jielian, 2024. "Liver mechanosignaling as a natural anti-hepatitis B virus mechanism," Nature Communications, Nature, vol. 15(1), pages 1-13, 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:13:y:2022:i:1:d:10.1038_s41467-022-34864-8. 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.