IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-32673-7.html
   My bibliography  Save this article

Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment

Author

Listed:
  • Yan Tang

    (Brigham and Women’s Hospital and Harvard Medical School)

  • David J. Kwiatkowski

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Elizabeth P. Henske

    (Brigham and Women’s Hospital and Harvard Medical School)

Abstract

mTORC1 is hyperactive in multiple cancer types1,2. Here, we performed integrative analysis of single cell transcriptomic profiling, paired T cell receptor (TCR) sequencing, and spatial transcriptomic profiling on Tuberous Sclerosis Complex (TSC) associated tumors with mTORC1 hyperactivity, and identified a stem-like tumor cell state (SLS) linked to T cell dysfunction via tumor-modulated immunosuppressive macrophages. Rapamycin and its derivatives (rapalogs) are the primary treatments for TSC tumors, and the stem-like tumor cells showed rapamycin resistance in vitro, reminiscent of the cytostatic effects of these drugs in patients. The pro-angiogenic factor midkine (MDK) was highly expressed by the SLS population, and associated with enrichment of endothelial cells in SLS-dominant samples. Inhibition of MDK showed synergistic benefit with rapamycin in reducing the growth of TSC cell lines in vitro and in vivo. In aggregate, this study suggests an autocrine rapamycin resistance mechanism and a paracrine tumor survival mechanism via immune suppression adopted by the stem-like state tumor cells with mTORC1 hyperactivity.

Suggested Citation

  • Yan Tang & David J. Kwiatkowski & Elizabeth P. Henske, 2022. "Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32673-7
    DOI: 10.1038/s41467-022-32673-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-32673-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-32673-7?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. Katie R. Martin & Wanding Zhou & Megan J. Bowman & Juliann Shih & Kit Sing Au & Kristin E. Dittenhafer-Reed & Kellie A. Sisson & Julie Koeman & Daniel J. Weisenberger & Sandra L. Cottingham & Steven T, 2017. "The genomic landscape of tuberous sclerosis complex," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    2. David Olmeda & Daniela Cerezo-Wallis & Erica Riveiro-Falkenbach & Paula C. Pennacchi & Marta Contreras-Alcalde & Nuria Ibarz & Metehan Cifdaloz & Xavier Catena & Tonantzin G. Calvo & Estela Cañón & Di, 2017. "Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine," Nature, Nature, vol. 546(7660), pages 676-680, June.
    3. Fernando Alvarez-Vasquez & Kellie J. Sims & L. Ashley Cowart & Yasuo Okamoto & Eberhard O. Voit & Yusuf A. Hannun, 2005. "Simulation and validation of modelled sphingolipid metabolism in Saccharomyces cerevisiae," Nature, Nature, vol. 433(7024), pages 425-430, January.
    4. Jordan A. Ramilowski & Tatyana Goldberg & Jayson Harshbarger & Edda Kloppmann & Marina Lizio & Venkata P. Satagopam & Masayoshi Itoh & Hideya Kawaji & Piero Carninci & Burkhard Rost & Alistair R. R. F, 2015. "A draft network of ligand–receptor-mediated multicellular signalling in human," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    5. Gioele La Manno & Ruslan Soldatov & Amit Zeisel & Emelie Braun & Hannah Hochgerner & Viktor Petukhov & Katja Lidschreiber & Maria E. Kastriti & Peter Lönnerberg & Alessandro Furlan & Jean Fan & Lars E, 2018. "RNA velocity of single cells," Nature, Nature, vol. 560(7719), pages 494-498, August.
    6. Nicola Alesi & Elie W. Akl & Damir Khabibullin & Heng-Jia Liu & Anna S. Nidhiry & Emma R. Garner & Harilaos Filippakis & Hilaire C. Lam & Wei Shi & Srinivas R. Viswanathan & Manrico Morroni & Shawn M., 2021. "TSC2 regulates lysosome biogenesis via a non-canonical RAGC and TFEB-dependent mechanism," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    7. Kseniya Obraztsova & Maria C. Basil & Ryan Rue & Aravind Sivakumar & Susan M. Lin & Alexander R. Mukhitov & Andrei I. Gritsiuta & Jilly F. Evans & Meghan Kopp & Jeremy Katzen & Annette Robichaud & Ele, 2020. "mTORC1 activation in lung mesenchyme drives sex- and age-dependent pulmonary structure and function decline," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Heng-Jia Liu & Heng Du & Damir Khabibullin & Mahsa Zarei & Kevin Wei & Gordon J. Freeman & David J. Kwiatkowski & Elizabeth P. Henske, 2023. "mTORC1 upregulates B7-H3/CD276 to inhibit antitumor T cells and drive tumor immune evasion," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

    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. Huanhuan Tan & Weixu Wang & Congjin Zhou & Yanfeng Wang & Shu Zhang & Pinglan Yang & Rui Guo & Wei Chen & Jinwen Zhang & Lan Ye & Yiqiang Cui & Ting Ni & Ke Zheng, 2023. "Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Christoph Ziegenhain & Rickard Sandberg, 2021. "BAMboozle removes genetic variation from human sequence data for open data sharing," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    3. Yoshiaki Yasumizu & Naganari Ohkura & Hisashi Murata & Makoto Kinoshita & Soichiro Funaki & Satoshi Nojima & Kansuke Kido & Masaharu Kohara & Daisuke Motooka & Daisuke Okuzaki & Shuji Suganami & Eriko, 2022. "Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. 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.
    5. Keyong Sun & Runda Xu & Fuhai Ma & Naixue Yang & Yang Li & Xiaofeng Sun & Peng Jin & Wenzhe Kang & Lemei Jia & Jianping Xiong & Haitao Hu & Yantao Tian & Xun Lan, 2022. "scRNA-seq of gastric tumor shows complex intercellular interaction with an alternative T cell exhaustion trajectory," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    6. Jeff Yat-Fai Chung & Philip Chiu-Tsun Tang & Max Kam-Kwan Chan & Vivian Weiwen Xue & Xiao-Ru Huang & Calvin Sze-Hang Ng & Dongmei Zhang & Kam-Tong Leung & Chun-Kwok Wong & Tin-Lap Lee & Eric W-F Lam &, 2023. "Smad3 is essential for polarization of tumor-associated neutrophils in non-small cell lung carcinoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Fabian Peisker & Maurice Halder & James Nagai & Susanne Ziegler & Nadine Kaesler & Konrad Hoeft & Ronghui Li & Eric M. J. Bindels & Christoph Kuppe & Julia Moellmann & Michael Lehrke & Christian Stopp, 2022. "Mapping the cardiac vascular niche in heart failure," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    8. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Ryuki Shimada & Yuzuru Kato & Naoki Takeda & Sayoko Fujimura & Kei-ichiro Yasunaga & Shingo Usuki & Hitoshi Niwa & Kimi Araki & Kei-ichiro Ishiguro, 2023. "STRA8–RB interaction is required for timely entry of meiosis in mouse female germ cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Daniel Dimitrov & Dénes Türei & Martin Garrido-Rodriguez & Paul L. Burmedi & James S. Nagai & Charlotte Boys & Ricardo O. Ramirez Flores & Hyojin Kim & Bence Szalai & Ivan G. Costa & Alberto Valdeoliv, 2022. "Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    11. Ana Belén Plata-Gómez & Lucía Prado-Rivas & Alba Sanz & Nerea Deleyto-Seldas & Fernando García & Celia Calle Arregui & Camila Silva & Eduardo Caleiras & Osvaldo Graña-Castro & Elena Piñeiro-Yáñez & Jo, 2024. "Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    12. Xiaojun Ren & Jianqing Liang & Yiming Zhang & Ning Jiang & Yuhui Xu & Mengdi Qiu & Yiqin Wang & Bing Zhao & Xiaojun Chen, 2022. "Single-cell transcriptomic analysis highlights origin and pathological process of human endometrioid endometrial carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    13. Gaofei Li & Yicong Sun & Immanuel Kwok & Liting Yang & Wanying Wen & Peixian Huang & Mei Wu & Jing Li & Zhibin Huang & Zhaoyuan Liu & Shuai He & Wan Peng & Jin-Xin Bei & Florent Ginhoux & Lai Guan Ng , 2024. "Cebp1 and Cebpβ transcriptional axis controls eosinophilopoiesis in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    14. Adele M. Alchahin & Shenglin Mei & Ioanna Tsea & Taghreed Hirz & Youmna Kfoury & Douglas Dahl & Chin-Lee Wu & Alexander O. Subtelny & Shulin Wu & David T. Scadden & John H. Shin & Philip J. Saylor & D, 2022. "A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Anneke Brümmer & Sven Bergmann, 2024. "Disentangling genetic effects on transcriptional and post-transcriptional gene regulation through integrating exon and intron expression QTLs," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    16. Ziyang Tang & Zuotian Li & Tieying Hou & Tonglin Zhang & Baijian Yang & Jing Su & Qianqian Song, 2023. "SiGra: single-cell spatial elucidation through an image-augmented graph transformer," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    17. Bibiana Costa & Jennifer Becker & Tobias Krammer & Felix Mulenge & Verónica Durán & Andreas Pavlou & Olivia Luise Gern & Xiaojing Chu & Yang Li & Luka Čičin-Šain & Britta Eiz-Vesper & Martin Messerle , 2024. "Human cytomegalovirus exploits STING signaling and counteracts IFN/ISG induction to facilitate infection of dendritic cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Patrick Aouad & Yueyun Zhang & Fabio Martino & Céline Stibolt & Simak Ali & Giovanna Ambrosini & Sendurai A. Mani & Kelly Maggs & Hazel M. Quinn & George Sflomos & Cathrin Brisken, 2022. "Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    19. Rachael G. Aubin & Emma C. Troisi & Javier Montelongo & Adam N. Alghalith & Maclean P. Nasrallah & Mariarita Santi & Pablo G. Camara, 2022. "Pro-inflammatory cytokines mediate the epithelial-to-mesenchymal-like transition of pediatric posterior fossa ependymoma," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    20. Yue Li & Tianfeng Lu & Pengzhen Dong & Jian Chen & Qiang Zhao & Yuying Wang & Tianheng Xiao & Honggang Wu & Quanyi Zhao & Hai Huang, 2024. "A single-cell atlas of Drosophila trachea reveals glycosylation-mediated Notch signaling in cell fate specification," Nature Communications, Nature, vol. 15(1), pages 1-18, 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_s41467-022-32673-7. 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.