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PDF file - 48K,Histological analysis of lungs from NOD-SCID mice bearing human melanoma xenografts following vehicle or dasatinib treatment

PDF file - 124K, Contains extended Materials and Methods for the manuscript

PDF file - 64K, Western blotting for phospho-EGFR in tumour xenografts

PDF file - 77K,Supplementary Figure Legends for Supplementary Figures S1 and S2

Supplementary Figures 1-2 from In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling

Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. (Cancer Res 2006; 66(19): 9483-91)

Supplementary Figure Legends 1-2 from In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling

Fibroblasts display extensive transcriptional heterogeneity, yet functional annotation and characterization of their heterocellular relationships remains incomplete. Using mass cytometry, we chart the stromal composition of 18 murine tissues and 5 spontaneous tumor models, with an emphasis on mesenchymal phenotypes. This analysis reveals extensive stromal heterogeneity across tissues and tumors, and identifies novel, coordinated, relationships between mesenchymal and immune cell subsets. Expression of CD105 demarks two stable and functionally distinct fibroblast lineages, that are ubiquitous in murine and human healthy tissues and tumors. Whereas CD105 positive fibroblasts are permissive for tumor growth in vivo, CD105 negative fibroblasts are highly tumor suppressive. This restrictive effect is entirely dependent on functional adaptive immunity, with a major contribution from type 1 conventional dendritic cells. Collectively, these results reveal two distinct fibroblast lineages conserved across tissues and species and highlight the importance of mesenchymal and immune cell interactions in restricting tumor growth., This upload consists of raw data as analysed in Hutton et al.