The paracrine Hedgehog-FGF axis mediates cancer stem cell plasticity in triple negative breast cancers — ASN Events
  1. Schedule
  2. Session 12: Poster Talks
  3. The paracrine Hedgehog-FGF axis mediates cancer stem cell plasticity in triple negative breast cancers

The paracrine Hedgehog-FGF axis mediates cancer stem cell plasticity in triple negative breast cancers (#108)

Aurélie Cazet 1 , Mun Hui 1 , Ben Elsworth 1 , Sunny Wu 1 , Caroline Cooper 1 2 , Jessica Yang 1 , Daniel Roden 1 , Niantao Deng 1 , Nicola Foreman 1 , Andrea McFarland 1 , Michael Samuel 3 , Sandra O'Toole 1 2 4 5 , Rosalía Caballero 6 , Miguel Martín 6 , Alex Swarbrick 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
  3. Tumour Microenvironment Laboratory, Centre for Cancer Biology University of South Australia, Adelaide, SA, Australia
  4. Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia
  5. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia
  6. Cancer Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain

Triple negative breast cancer (TNBC) is a major therapeutic challenge, characterised by rapid relapse, drug resistance and an absence of targeted therapies. Breast cancer progression is associated with a marked stromal activation, and numerous factors provided by the stroma are critical for tumour growth and survival. However, there is little understanding of the molecular signals controlling stromal recruitment and activation and its relevance to disease aetiology and therapeutic response.

The Hedgehog (Hh) morphogenic pathway is a conserved system for regulating development and cell fate. The paracrine Hh signalling pathway has been unambiguously linked to development and aggressiveness of the TNBC subtype. Using single cell transcriptomics we now demonstrate that Hh ligand produced by neoplastic cells leads to Hh pathway activation exclusively in the cancer-associated fibroblast (CAFs) population. Hh-activated CAFs subsequently orchestrate an intricate crosstalk with the adjacent breast cancer (BrCa) compartment via remodelling of the collagen matrix and secretion of FGF5. This expands BrCa subpopulations are enriched for stem cell-like properties, marked by the expression of the mammary stem markers CK6 and ALDH1, specifically at the tumour-stromal interface. 

Importantly, treatment of mouse models of TNBC with Hh pathway inhibitors significantly reduces the expression of FGF5 by CAFs and stem cell markers by the neoplastic population. Furthermore, combination therapy of Smoothened inhibitors (SMOi) plus docetaxel chemotherapy dramatically improved survival and reduced metastatic burden in mice bearing patient-derived xenografts (PDXs), compared to single agent arms. In a phase I clinical trial, we show that the SMOi Sonidegib can be safely administered with docetaxel to patients with metastatic TNBC. Two patients with Hh pathway activation showed evidence of clinical benefit, with one patient experiencing a complete response.

These studies identify the Hh-FGF axis as a novel paracrine mediator of cancer stem cell plasticity and strongly highlight an exciting new therapeutic opportunity targeting both tumour cells and their surrounding signalling support in TNBC.