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.

Retracted: Long noncoding RNA MALAT1 promotes the stemness of esophageal squamous cell carcinoma by enhancing YAP transcriptional activity

“…In addition, knockdown of MALAT1 attenuated the stemness of ESCC cells, as evidenced by a decrease in spheroid formation capacity, stemness marker expression and aldehyde dehydrogenase 1 activity. Smoothened inhibitors could target breast CSCs and thus sensitize TNBC cells to docetaxel, improving survival and reducing metastatic burden in the phase I clinical trial EDALINE [5]. Notably, knockdown of MALAT1 enhanced the radiosensitivity and chemosensitivity of ESCC cells.…”

Concise Review: Targeting Cancer Stem Cells and Their Supporting Niche Using Oncolytic Viruses

“…As M2 macrophages express CD206 in hypoxic niches , a virally encoded CD206‐CD3 BiTE could potentially activate T cells in the presence of M2 type TAMs. Recent studies have shed light on the ability of CSCs to communicate with TME components such as CAFs , via exosomes and other secreted factors. A major challenge to many therapies involves overcoming CAF‐mediated effects in the TME, such as their promotion of tumor growth, angiogenesis, extracellular matrix degradation and EMT .…”

“…Recent studies have shed light on the ability of CSCs to communicate with TME components such as CAFs , via exosomes and other secreted factors. A major challenge to many therapies involves overcoming CAF‐mediated effects in the TME, such as their promotion of tumor growth, angiogenesis, extracellular matrix degradation and EMT . In recent studies, a fibroblast‐activating protein‐CD3 BiTE has been encoded in an oncolytic vaccinia virus or adenovirus to target immunosuppressive stromal cells .…”

The Mini‐Organo: A rapid high‐throughput 3D coculture organotypic assay for oncology screening and drug development

“…Using SHG-generated images, orientation of collagen fibres can be assessed ( Figure 2G [bottom]). 10,[58][59][60][61] In addition, collagen fibre network organization can also be characterised using grey-level cooccurrence matrix (GLCM) analysis. 10,58,59,[61][62][63] This method provides a readout of the texture of a sample by quantifying the similarity between pixels across an image 64 (Figure 2H, data example shown is from blebbistatin treated CAFs [ Figure 4B]).…”

“…This approach allows for high resolution imaging of collagen fibres. Using SHG‐generated images, orientation of collagen fibres can be assessed (Figure G [bottom]) . In addition, collagen fibre network organization can also be characterised using grey‐level co‐occurrence matrix (GLCM) analysis .…”