It is becoming accepted that metastases functions as an ecosystem, where cancer cells co-operate with various factors of the microenvironment (stroma cells, extracellular matrix and soluble mediators) to assure the best conditions for tumor growth and survival. The complexity and plasticity within such cancer ecosystem, creates both challenges and new opportunities for anti-metastatic therapy.
Our project group focuses on understanding how cancer cells exploit the stromal cells, how stromal factors influence phenotypic and functional characteristics of the cancer, and how this affects metastasis and drug resistance. We aim to understand biological mechanisms behind such influence, and thereby, to reveal candidate targets for therapeutic intervention. We use malignant melanoma as a model, since it represent one of the most metastatic and resistant human cancers.
1) Stromal cells as modulators of cancer phenotype and response to therapy
Several recent studies, including ours, reported that fibroblasts make adjacent melanoma cells resistant to vemurafenib, a targeted drug against mutated BRAF used in the clinic. We demonstrated that this effect was linked to fibroblasts-induced phenotype switching in melanoma cells, which acquired the invasive mesenchymal-like de-differentiated phenotype (Seip et al., Oncotarget 2017). This data strengthens the notion that fibroblasts promote phenotypic heterogeneity within a tumor, and raises the need for phenotype-directed therapies. To tailor such therapies, we are studying signaling and metabolic preferences of each phenotype. Through inhibition of the preferred signaling or metabolic pathways, we aim to eliminated the stroma-supported mesenchymal-like cancer cells. This project proposes the need for combination treatments that target both, stroma-supported and non-supported counterparts of the tumor.
2) An association between cancer phenotype and inflammatory factors
Previously we have shown that a pro-inflammatory soluble factor S100A4 is enriched in the microenvironment of metastatic lesions. Upon stimulation with extracellular S100A4, melanoma cells acquired the mesenchymal phenotype (Bettum et al., Cancer Letters 2016) and enhanced production of pro-inflammatory cytokines (Bettum et al., Cancer Letters 2014). The secreted cytokines mediated activation of inflammatory cells i.e. monocytes/macrophages, which further promoted pro-metastatic properties of melanoma (Bettum et al., Cancer Letters 2014). Our working hypothesis is that the invasive phenotype might benefit from the inflammatory milieu and, therefore, is more prone to produce cytokines and engage inflammatory cells. To validate this hypothesis, we are currently studying the association between cancer phenotype and its pro-inflammatory properties, communication with macrophages, and molecular mediators involved. Similar studies are also performed on breast cancer leaded by Prof. Gunhild M. Mælandsmo