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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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

doi

10.1038/s41467-018-05220-6

subject

Has Abstract

pub_date

2018-07-24 00:00:00

pages

2897

issue

1

issn

2041-1723

pii

10.1038/s41467-018-05220-6

journal_volume

9

pub_type

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