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Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

Author

Listed:
  • Aurélie S. Cazet

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Mun N. Hui

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    The Chris O’ Brien Lifehouse
    Royal Prince Alfred Hospital)

  • Benjamin L. Elsworth

    (University of Bristol)

  • Sunny Z. Wu

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Daniel Roden

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Chia-Ling Chan

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre)

  • Joanna N. Skhinas

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre)

  • Raphaël Collot

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre)

  • Jessica Yang

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre)

  • Kate Harvey

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre)

  • M. Zahied Johan

    (SA Pathology and the University of South Australia
    University of Adelaide)

  • Caroline Cooper

    (University of Queensland)

  • Radhika Nair

    (Rajiv Gandhi Centre for Biotechnology)

  • David Herrmann

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Andrea McFarland

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre)

  • Niantao Deng

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Manuel Ruiz-Borrego

    (Hospital Universitario Virgen del Rocío)

  • Federico Rojo

    (Hospital Universitario Fundación Jiménez Díaz)

  • José M. Trigo

    (IBIMA)

  • Susana Bezares

    (Spanish Breast Cancer Group)

  • Rosalía Caballero

    (Spanish Breast Cancer Group)

  • Elgene Lim

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney
    St Vincent’s Hospital)

  • Paul Timpson

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Sandra O’Toole

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    Royal Prince Alfred Hospital)

  • D. Neil Watkins

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney
    St Vincent’s Hospital)

  • Thomas R. Cox

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

  • Michael S. Samuel

    (SA Pathology and the University of South Australia
    University of Adelaide)

  • Miguel Martín

    (Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII)

  • Alexander Swarbrick

    (Garvan Institute of Medical Research
    The Kinghorn Cancer Centre
    UNSW Sydney)

Abstract

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.

Suggested Citation

  • Aurélie S. Cazet & Mun N. Hui & Benjamin L. Elsworth & Sunny Z. Wu & Daniel Roden & Chia-Ling Chan & Joanna N. Skhinas & Raphaël Collot & Jessica Yang & Kate Harvey & M. Zahied Johan & Caroline Cooper, 2018. "Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05220-6
    DOI: 10.1038/s41467-018-05220-6
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    Cited by:

    1. Karl Smith-Byrne & Åsa Hedman & Marios Dimitriou & Trishna Desai & Alexandr V. Sokolov & Helgi B. Schioth & Mine Koprulu & Maik Pietzner & Claudia Langenberg & Joshua Atkins & Ricardo Cortez Penha & J, 2024. "Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Michael Papanicolaou & Amelia L. Parker & Michelle Yam & Elysse C. Filipe & Sunny Z. Wu & Jessica L. Chitty & Kaitlin Wyllie & Emmi Tran & Ellie Mok & Audrey Nadalini & Joanna N. Skhinas & Morghan C. , 2022. "Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Masud, M.A. & Kim, Eunjung, 2024. "Theoretical understanding of evolutionary dosing following tumor dynamics," Chaos, Solitons & Fractals, Elsevier, vol. 179(C).

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