Abstract The tumor microenvironment (TME) promotes proliferation, drug resistance, and invasiveness of cancer cells. Therapeutic targeting of the TME is an attractive strategy to improve outcomes for patients, particularly in aggressive cancers such as triple-negative breast cancer (TNBC) that have a rich stroma and limited targeted therapies. However, lack of preclinical human tumor models for mechanistic understanding of tumor–stromal interactions has been an impediment to identify effective treatments against the TME. To address this need, we developed a three-dimensional organotypic tumor model to study interactions of patient-derived cancer-associated fibroblasts (CAF) with TNBC cells and explore potential therapy targets. We found that CAFs predominantly secreted hepatocyte growth factor (HGF) and activated MET receptor tyrosine kinase in TNBC cells. This tumor–stromal interaction promoted invasiveness, epithelial-to-mesenchymal transition, and activities of multiple oncogenic pathways in TNBC cells. Importantly, we established that TNBC cells become resistant to monotherapy and demonstrated a design-driven approach to select drug combinations that effectively inhibit prometastatic functions of TNBC cells. Our study also showed that HGF from lung fibroblasts promotes colony formation by TNBC cells, suggesting that blocking HGF-MET signaling potentially could target both primary TNBC tumorigenesis and lung metastasis. Overall, we established the utility of our organotypic tumor model to identify and therapeutically target specific mechanisms of tumor–stromal interactions in TNBC toward the goal of developing targeted therapies against the TME. Implications: Leveraging a state-of-the-art organotypic tumor model, we demonstrated that CAFs-mediated HGF-MET signaling drive tumorigenic activities in TNBC and presents a therapeutic target.
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Cowpea Mosaic Virus Immunotherapy Combined with Cyclophosphamide Reduces Breast Cancer Tumor Burden and Inhibits Lung Metastasis
Patients with metastatic triple‐negative breast cancer (TNBC) have a poor prognosis, so new therapies or drug combinations that achieve more effective and durable responses are urgently needed. Here, a combination therapy using cowpea mosaic virus (CPMV) and low doses of cyclophosphamide (CPA) is developed with remarkable synergistic efficacy against 4T1 mouse tumors in vivo. The combination therapy not only attenuates the growth of primary tumor and increases survival, but also suppresses distant tumor growth and reduces lung metastasis. Mechanistic analysis indicates that the combination of CPMV and CPA increases the secretion of several cytokines, activates antigen‐presenting cells, increases the abundance of tumor infiltrating T cells, and systematically reverses the immunosuppression. These results show that the combination of CPMV in situ vaccination with chemotherapy may become a potent new strategy for the treatment of TNBC.
more » « less- NSF-PAR ID:
- 10460346
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Science
- Volume:
- 6
- Issue:
- 16
- ISSN:
- 2198-3844
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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