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Cited by 437Hedgehog Signaling Pathway StudiesCancer Cells and MetastasisBreast Cancer Treatment Studies

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

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Cazet, Aurélie S., Hui, Mun N., Elsworth, Benjamin L., Wu, Sunny Z., Roden, Daniel, Chan, Chia-Ling, Skhinas, Joanna N., Collot, Raphaël +21 more·2018·Nature Communications
DOI 10.1038/s41467-018-05220-6PMC PMC6057940

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Abstract

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), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized 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. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC. SIGNIFICANCE Compared to other breast cancer subtypes, TNBCs are associated with significantly worse patient outcomes. Standard of care systemic treatment for patients with non-BRCA1/2 positive TNBC is cytotoxic chemotherapy. However, the failure of 70% of treated TNBCs to attain complete pathological response reflects the relative chemoresistance of these tumors. New therapeutic strategies are needed to improve patient survival and quality of life. Here, we provide new insights into the dynamic interactions between heterotypic cells within a tumor. Specifically, we establish the mechanisms by which CAFs define cancer cell phenotype and demonstrate that the bidirectional CAF-cancer cell crosstalk can be successfully targeted in mice and humans using anti-stromal therapy.

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  • Production of TGFβ, LIF, GAS6, FGF5, GDF15 and HGF promotes invasive and proliferative behaviour in cancer cells.

    “The production of TGFβ, leukaemia inhibitory factor (LIF), growth arrest-specific protein 6 (GAS6), fibroblast growth factor 5 (FGF5), growth differentiation factor 15 (GDF15) and hepatocyte growth factor (HGF) promotes invasive and proliferative behaviour in cancer cells52,109–112.”

    From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [110]

    The Results section on the paracrine Hh–FGF5 axis (page unavailable) reports that FGF5 produced by activated stromal cells increased proliferation of M6 breast cancer cells under serum and growth-factor deprivation. It does not establish that FGF5 promotes invasion or support the listed effects of TGFβ, LIF, GAS6, GDF15, and HGF. (LLM, conf=0.86)

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Authors
Cazet, A. S., Hui, M. N., Elsworth, B. L., Wu, S. Z., Roden, D., Chan, C.-L., Skhinas, J. N., Collot, R., Yang, J., Harvey, K., Johan, M. Z., Cooper, C., Nair, R., Herrmann, D., McFarland, A., Deng, N., Ruiz-Borrego, M., Rojo, F., Trigo, J. M., Bezares, S., Caballero, R., Lim, E., Timpson, P., O’Toole, S., Watkins, D. N., Cox, T. R., Samuel, M. S., Martín, M., & Swarbrick, A.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • University of Bristol (GB)
  • South Australia Pathology (AU)
  • The University of Queensland (AU)
  • Rajiv Gandhi Centre for Biotechnology (IN)
  • Hospital Universitario Fundación Jiménez Díaz (ES)
  • Hospital Clínico Universitario Virgen de la Victoria (ES)
  • GEICAM – Spanish Breast Cancer Group (ES)
  • Instituto de Salud Carlos III (ES)
Corresponding author
Swarbrick, Alexander
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-07-24
Volume
9
Issue
1
Pages
2897-2897
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-05220-6
PMC
PMC6057940
OpenAlex
W2949633340
Cited by
437
References
8
Citations by year
2026: 23 · 2025: 41 · 2024: 58 · 2023: 56 · 2022: 58 · 2021: 93 · 2020: 56 · 2019: 42 · 2018: 10
FWCI
18.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
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  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
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  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
  • UniSA Research Outputs Repository (University of South Australia) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
Funders
  • Pfizer
  • Pfizer Australia
  • National Breast Cancer Foundation
  • Petre Foundation
  • Royal Adelaide Hospital
  • Medical Research Council
  • Australian Research Council
  • National Health and Medical Research Council
  • Cancer Council South Australia
  • Royal Adelaide Hospital Research Fund
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
triple-negative breast cancer, stromal remodeling, cancer-associated fibroblasts, Hedgehog signaling, cancer stem cells, chemoresistance, FGF5, Smoothened inhibitors, sonidegib, docetaxel, metastasis, patient-derived xenografts
MeSH terms
Docetaxel, Adult, Aged, Anilides, Animals, Antineoplastic Combined Chemotherapy Protocols, Biphenyl Compounds, Female, Humans, Middle Aged, Pyridines, Neoplastic Stem Cells, Mice, SCID, Mice, Inbred NOD, Treatment Outcome, Mice, Knockout, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Triple Negative Breast Neoplasms

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