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

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; Radhika Nair; David Herrmann; Andrea McFarland; Niantao Deng; Manuel Ruiz-Borrego; Federico Rojo; José M. Trigo; Susana Bezares; Rosalía Caballero; Elgene Lim; Paul Timpson; Sandra O’Toole; D. Neil Watkins; Thomas R. Cox; Michael S. Samuel; Miguel Martín; Alexander Swarbrick

doi:10.1038/s41467-018-05220-6

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

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, Radhika Nair, David Herrmann, Andrea McFarland, Niantao Deng, Manuel Ruiz-Borrego, Federico Rojo, José M. Trigo, Susana BezaresRosalía Caballero, Elgene Lim, Paul Timpson, Sandra O’Toole, D. Neil Watkins, Thomas R. Cox, Michael S. Samuel, Miguel Martín, Alexander Swarbrick^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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.

Original language	English
Article number	2897
Number of pages	18
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-05220-6
Publication status	Published - 24 Jul 2018

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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., ... Swarbrick, A. (2018). Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nature Communications, 9, Article 2897. https://doi.org/10.1038/s41467-018-05220-6

@article{aca3263c124442af81120596a597ce9a,

title = "Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer",

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.",

author = "Cazet, {Aur{\'e}lie S.} and Hui, {Mun N.} and Elsworth, {Benjamin L.} and Wu, {Sunny Z.} and Daniel Roden and Chan, {Chia Ling} and Skhinas, {Joanna N.} and Rapha{\"e}l Collot and Jessica Yang and Kate Harvey and Johan, {M. Zahied} and Caroline Cooper and Radhika Nair and David Herrmann and Andrea McFarland and Niantao Deng and Manuel Ruiz-Borrego and Federico Rojo and Trigo, {Jos{\'e} M.} and Susana Bezares and Rosal{\'i}a Caballero and Elgene Lim and Paul Timpson and Sandra O{\textquoteright}Toole and Watkins, {D. Neil} and Cox, {Thomas R.} and Samuel, {Michael S.} and Miguel Mart{\'i}n and Alexander Swarbrick",

year = "2018",

month = jul,

day = "24",

doi = "10.1038/s41467-018-05220-6",

language = "English",

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journal = "Nature Communications",

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Cazet, AS, Hui, MN, Elsworth, BL, Wu, SZ, Roden, D, Chan, CL, Skhinas, JN, Collot, R, Yang, J, Harvey, K, Johan, MZ, Cooper, C, Nair, R, Herrmann, D, McFarland, A, Deng, N, Ruiz-Borrego, M, Rojo, F, Trigo, JM, Bezares, S, Caballero, R, Lim, E, Timpson, P, O’Toole, S, Watkins, DN, Cox, TR, Samuel, MS, Martín, M & Swarbrick, A 2018, 'Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer', Nature Communications, vol. 9, 2897. https://doi.org/10.1038/s41467-018-05220-6

TY - JOUR

T1 - Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

AU - Cazet, Aurélie S.

AU - Hui, Mun N.

AU - Elsworth, Benjamin L.

AU - Wu, Sunny Z.

AU - Roden, Daniel

AU - Chan, Chia Ling

AU - Skhinas, Joanna N.

AU - Collot, Raphaël

AU - Yang, Jessica

AU - Harvey, Kate

AU - Johan, M. Zahied

AU - Cooper, Caroline

AU - Nair, Radhika

AU - Herrmann, David

AU - McFarland, Andrea

AU - Deng, Niantao

AU - Ruiz-Borrego, Manuel

AU - Rojo, Federico

AU - Trigo, José M.

AU - Bezares, Susana

AU - Caballero, Rosalía

AU - Lim, Elgene

AU - Timpson, Paul

AU - O’Toole, Sandra

AU - Watkins, D. Neil

AU - Cox, Thomas R.

AU - Samuel, Michael S.

AU - Martín, Miguel

AU - Swarbrick, Alexander

PY - 2018/7/24

Y1 - 2018/7/24

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-018-05220-6

DO - 10.1038/s41467-018-05220-6

M3 - Article (Academic Journal)

C2 - 30042390

AN - SCOPUS:85050625637

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 2897

ER -

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

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