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

Thomas R. Cox, July 2018

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

The Matrix and Metastasis lab is excited to have been part of a study led by A/Prof Alex Swarbrick and colleagues which has just been published in Nature Communications.

The work looked at the communication between breast cancer cells and surrounding non-cancer cells which are important in helping the tumour to grow. Using mouse models, and also a Phase I clinical trial, the team showed that the communication netween breast cancer cells and cancer associated fibroblasts (CAFs) in triple negative breast tumour facilitates the adoption of “stem cell-like” properties which help the tumour grow, but also to become resistant the chemotherapy. Blocking this communication slowed down tumour growth and increased the effectiveness of chemotherapy.

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.

Links

View the entry on PubMed
View the article on the Nature Communications website
Click here to read the .pdf

Citation

Cazet A et al. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
Nature Communications (2018) | doi: 10.1038/s41467-018-05220-6

Funding

This work was supported by funding from the National Health and Medical Research Council (NHMRC) of Australia, the McMurtrie family, Perpetual Trustees, the Estate of the late RT Hall and Novartis. A.S. is the recipient of a Career Development Award from the NHMRC. M.N.H. is a recipient of the following awards: 2013 Pfizer Australia Cancer Research Grant, Australia Postgraduate Award, Sydney Catalyst Top-Up Scholarship and Sydney Breast Cancer Foundation Fellowship. D.N.W. acknowledges the Petre Foundation. T.R.C. is the recipient of a New Investigator Award from the NHMRC. M.S. is supported by a Future Fellowship from the Australian Research Council and Project Grant funding from the NHMRC, the Cancer Council South Australia and the Royal Adelaide Hospital Research Fund. The Zeiss LSM710 two-photon system used for SHG analysis was purchased with assistance from the Health Service Charitable Gifts Board of South Australia. P.T. is the recipient of Len Ainsworth Research Fellowship. S.O.T. is supported by NBCF practitioner fellowship and also gratefully acknowledges the support of the Sydney Breast Cancer Foundation, the Tag family, Mr David Paradice, ICAP and the O’Sullivan family and the estate of the late Kylie Sinclair.