Global and single-cell proteomics view of the co-evolution between neural progenitors and breast cancer cells in a co-culture model.

Tumor neurogenesis, a process by which new nerves invade tumors, is a growing area of interest in cancer research. Nerve presence has been linked to aggressive features of various solid tumors, including breast and prostate cancer. A recent study suggested that the tumor microenvironment may influence cancer progression through recruitment of neural progenitor cells from the central nervous system. However, the presence of neural progenitors in human breast tumors has not been reported. Here, we investigate the presence of Doublecortin (DCX) and Neurofilament-Light (NFL) co-expressing (DCX+/NFL+) cells in patient breast cancer tissue using Imaging Mass Cytometry. To map the interaction between breast cancer cells and neural progenitor cells further, we created an in vitro model mimicking breast cancer innervation, and characterized using mass spectrometry-based proteomics on the two cell types as they co- evolved in co-culture. Our results indicate stromal presence of DCX+/NFL+ cells in breast tumor tissue from a cohort of 107 patient cases, and that neural interaction contribute to drive a more aggressive breast cancer phenotype in our co-culture models. Our results support that neural involvement plays an active role in breast cancer and warrants further studies on the interaction between nervous system and breast cancer progression.

CCT196969 effectively inhibits growth and survival of melanoma brain metastasis cells.

Melanomas frequently metastasize to the brain. Despite recent progress in the treatment of melanoma brain metastasis, therapy resistance and relapse of disease remain unsolved challenges. CCT196969 is a SRC family kinase (SFK) and Raf proto-oncogene, serine/threonine kinase (RAF) inhibitor with documented effects in primary melanoma cell lines in vitro and in vivo. Using in vitro cell line assays, we studied the effects of CCT196969 in multiple melanoma brain metastasis cell lines. The drug effectively inhibited proliferation, migration, and survival in all examined cell lines, with viability IC50 doses in the range of 0.18-2.6 µM. Western blot analysis showed decreased expression of p-ERK, p-MEK, p-STAT3 and STAT3 upon CCT196969 treatment. Furthermore, CCT196969 inhibited viability in two B-Raf Proto-Oncogene (BRAF) inhibitor resistant metastatic melanoma cell lines. Further in vivo studies should be performed to determine the treatment potential of CCT196969 in patients with treatment-naïve and resistant melanoma brain metastasis.

Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways.

Melanomas have a high potential to metastasize to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extracranial melanomas. However, few patients with melanoma brain metastasis (MBM) respond effectively to these treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved for the treatment of non-skin-related cancers. The drug targets several of the proteins that are known to be dysregulated in melanomas. The anti-tumor activity of cabozantinib was investigated using three human MBM cell lines. Cabozantinib treatment decreased the viability of all cell lines both when grown in monolayer cultures and as tumor spheroids. The in vitro cell migration was also inhibited and apoptosis was induced by cabozantinib. The phosphorylated RTKs p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the MBM cells after cabozantinib treatment. Western blot validated these results and showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Further investigations are warranted to elucidate the therapeutic potential of cabozantinib for patients with MBM.