1. TP Tumor-Stroma Interactions Tumor and plasma proteomics insights into tumor stroma interactions 109 luminal human breast cancer specimens+plasma o high levels of Amphiregulin (AREG) in undissected tumor specimens o EGF not detectable in tumor specimens: Human plasma samples (healthy & diseased) show high but variable yields of HRG, BTC, EGF and many other ligands o Tumor VEGFA levels correlate with risk/grading o Tumor HGF shows inverse correlation with risk/grading o Stromal downregulation of Caveolin-1 correlates with risk VEGFA HGF

2. TP Tumor-Stroma Interactions Tumor and plasma proteomics insights into tumor stroma interactions 109 luminal human breast cancer specimens+plasma o Molecular impact of e.g. AREG and EGF on (A) downstream signaling, (B) transcription factor activation/expression and (C) induction/repression of miRs in model systems of human breast cancer o Systems biology of crosstalk between InsulinR/IGFR and EGFR signals, integration of cytokine signaling o What initiates the downregulation of Caveolin-1 in stroma cells (CAF)? o Proteome profiling of other molecular subtypes of human breast cancer (HER2 pos., TN, basal)

3. Inflammatory cytokines IL-1, IL6, IL-8, TNFα, TGFβ, VEGFA, … Growth factors AREG, EGF, HGF, IGF-1… WP2 Modeling of ligand-specific signaling (e.g. EGF vs. AREG), integration of insulin and cytokine signaling Readout: (1) mRNA/Illumina (2) RPPA (3) TF enrichment for RPPA (nuclei)  identify cooperative effects between signaling nodes, molecular subtype-specific  validation of crosstalk effects in co-culture models „kinase dynamics involved in transcription factor activation and feedback controls of signaling systems“ WP3 data-driven development of „tumor stroma“ treatment concepts  validation in co-culture models  validation in human tumors (IHC, RPPA) WP1 Cytokine, proteome, & GF profiles of human breast cancer specimens → identify targets for WP2 Basal, HER2+, triple negative breast cancer TP Tumor-Stroma Interactions DNA damage cell cycle Hedgehog TGFb/SMAD PI3K/PTEN cell adhesion apoptosis NOTCH JAK/STAT metabolic transformation WNT RAS/RAF 12 core pathways involved in cancer fatty tissue blood vessels WP4 validate „tumor stroma“ treatment concepts in mouse models → analyse mouse tumors, mouse plasma proteomics → explant tumors/cell culture, measure cytokines, growth factors