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         description: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. Stromal cell recruitment, activation and crosstalk with cancer cells is poorly understood. Here, the authors demonstrate that cancer cell-derived Hedgehog ligand  triggers stromal remodeling that in turn induces a cancer-stem-cell like, drug-resistant phenotype of nearby cancer cells while treatment with smoothened inhibitors reverses these phenotypes.
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      headline:Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
      description: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. Stromal cell recruitment, activation and crosstalk with cancer cells is poorly understood. Here, the authors demonstrate that cancer cell-derived Hedgehog ligand  triggers stromal remodeling that in turn induces a cancer-stem-cell like, drug-resistant phenotype of nearby cancer cells while treatment with smoothened inhibitors reverses these phenotypes.
      datePublished:2018-07-24T00:00:00Z
      dateModified:2018-07-24T00:00:00Z
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         Breast cancer
         Cancer microenvironment
         Cancer stem cells
         Science
         Humanities and Social Sciences
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            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Chris O’ Brien Lifehouse
            address:
               name:The Chris O’ Brien Lifehouse, Camperdown, Australia
               type:PostalAddress
            type:Organization
            name:Royal Prince Alfred Hospital
            address:
               name:Royal Prince Alfred Hospital, Camperdown, Australia
               type:PostalAddress
            type:Organization
      name:Benjamin L. Elsworth
      affiliation:
            name:University of Bristol
            address:
               name:MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
               type:PostalAddress
            type:Organization
      name:Sunny Z. Wu
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Daniel Roden
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Chia-Ling Chan
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Joanna N. Skhinas
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Raphaël Collot
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Jessica Yang
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Kate Harvey
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:M. Zahied Johan
      affiliation:
            name:SA Pathology and the University of South Australia
            address:
               name:Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia
               type:PostalAddress
            type:Organization
            name:University of Adelaide
            address:
               name:Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, Australia
               type:PostalAddress
            type:Organization
      name:Caroline Cooper
      affiliation:
            name:University of Queensland
            address:
               name:Pathology Queensland and School of Medicine, University of Queensland, St Lucia, Australia
               type:PostalAddress
            type:Organization
      name:Radhika Nair
      affiliation:
            name:Rajiv Gandhi Centre for Biotechnology
            address:
               name:Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
               type:PostalAddress
            type:Organization
      name:David Herrmann
      url:http://orcid.org/0000-0002-9514-7501
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Andrea McFarland
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Niantao Deng
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Manuel Ruiz-Borrego
      affiliation:
            name:Hospital Universitario Virgen del Rocío
            address:
               name:Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
               type:PostalAddress
            type:Organization
      name:Federico Rojo
      affiliation:
            name: Hospital Universitario Fundación Jiménez Díaz
            address:
               name:Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:José M. Trigo
      affiliation:
            name:IBIMA
            address:
               name:Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, Málaga, Spain
               type:PostalAddress
            type:Organization
      name:Susana Bezares
      affiliation:
            name:Spanish Breast Cancer Group
            address:
               name:GEICAM, Spanish Breast Cancer Group, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Rosalía Caballero
      affiliation:
            name:Spanish Breast Cancer Group
            address:
               name:GEICAM, Spanish Breast Cancer Group, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Elgene Lim
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:St Vincent’s Hospital
            address:
               name:St Vincent’s Hospital, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Paul Timpson
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Sandra O’Toole
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:Royal Prince Alfred Hospital
            address:
               name:Royal Prince Alfred Hospital, Camperdown, Australia
               type:PostalAddress
            type:Organization
      name:D. Neil Watkins
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:St Vincent’s Hospital
            address:
               name:St Vincent’s Hospital, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Thomas R. Cox
      url:http://orcid.org/0000-0001-9294-1745
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      name:Michael S. Samuel
      url:http://orcid.org/0000-0001-7880-6379
      affiliation:
            name:SA Pathology and the University of South Australia
            address:
               name:Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia
               type:PostalAddress
            type:Organization
            name:University of Adelaide
            address:
               name:Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, Australia
               type:PostalAddress
            type:Organization
      name:Miguel Martín
      affiliation:
            name:Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII
            address:
               name:Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain
               type:PostalAddress
            type:Organization
      name:Alexander Swarbrick
      affiliation:
            name:Garvan Institute of Medical Research
            address:
               name:Garvan Institute of Medical Research, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:The Kinghorn Cancer Centre
            address:
               name:The Kinghorn Cancer Centre, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
            name:UNSW Sydney
            address:
               name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:The Chris O’ Brien Lifehouse, Camperdown, Australia
      name:Royal Prince Alfred Hospital, Camperdown, Australia
      name:MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia
      name:Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, Australia
      name:Pathology Queensland and School of Medicine, University of Queensland, St Lucia, Australia
      name:Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
      name:Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
      name:Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, Málaga, Spain
      name:GEICAM, Spanish Breast Cancer Group, Madrid, Spain
      name:GEICAM, Spanish Breast Cancer Group, Madrid, Spain
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:St Vincent’s Hospital, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:Royal Prince Alfred Hospital, Camperdown, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:St Vincent’s Hospital, Darlinghurst, Australia
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia
      name:Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, Australia
      name:Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, Australia
      name:Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain
      name:Garvan Institute of Medical Research, Darlinghurst, Australia
      name:The Kinghorn Cancer Centre, Darlinghurst, Australia
      name:St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, Australia

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