Editors' ChoiceCancer

The stroma gives tumors a dose of drug tolerance

Sci. Signal.  28 Apr 2015:
Vol. 8, Issue 374, pp. ec105
DOI: 10.1126/scisignal.aab3803

Melanomas with activating mutations in the kinase BRAF often develop resistance to targeted BRAF inhibitors. Using intravital microscopy and a BRAF pathway biosensor to monitor the response of melanoma cells to a BRAF inhibitor in mice, Hirata et al. found that tumor cells evaded the cytotoxicity of the drug with the help of surrounding fibroblasts. Melanoma cells exhibited sensitivity to a BRAF inhibitor (PLX4720) in culture but resistance when grown subcutaneously in mice. Imaging showed that inhibition of the BRAF pathway by PLX4720 in the tumor cells occurred only in the first few hours of treatment in mice, but then rapidly became refractory, and that these resistant cells were located in regions of the tumor with a high abundance of host macrophages and stromal fibroblasts. Tumor tissue explants embedded in collagen matrix were resistant to PLX4720-induced cell death, whereas pure melanoma cell spheroids were not. When cocultured in collagen with melanoma-associated fibroblasts (but not macrophages) isolated from patients, drug-sensitive melanoma spheroids became resistant to the cytotoxic effects of PLX4720 and exhibited invasive behavior. Collagen gel contraction assays showed that PLX4720 induced extracellular matrix (ECM) remodeling activity in patient-derived fibroblasts but not in mouse lung or human dermal fibroblasts in culture. Some tumor samples from patients with BRAF inhibitor-resistant melanoma also exhibited matrix remodeling and increased density of fibroblasts in the stroma. Increasing the stiffness or the abundance of fibronectin in the collagen gel decreased the sensitivity of mouse melanoma spheroids to PLX4720. Either changing the ECM composition and stiffness of melanoma spheroid cultures or treating melanoma-fibroblasts cocultures with PLX4720 induced the reorganization of integrin-β1 into focal adhesions and the phosphorylation of focal adhesion kinase (FAK) in melanoma cells. Combining PLX4720 with an FAK inhibitor induced tumor regression in both mouse melanoma allografts and patient-derived xenografts. Thus, this study provides a mechanism for targeting the effects of the microenvironment to limit drug resistance in tumors (see also Frame and Serrels).

E. Hirata, M. Romina Girotti, A. Viros, S. Hooper, B. Spencer-Dene, M. Matsuda, J. Larkin, R. Marais, E. Sahai, Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27, 574–588 (2015). [PubMed]

M. C. Frame, A. Serrels, FAK to the rescue: Activated stroma promotes a “safe haven” for BRAF-mutant melanoma cells by inducing FAK signaling. Cancer Cell 27, 429–431 (2015). [PubMed]

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