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

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  • 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
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    1. 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.
    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. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
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    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.

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