Cancer cell signaling of MACC1 and S100A4 for mechanism-based interventions
MACC1 was newly discovered in our group acting as a decisive driver for tumor progression and metastasis for a large variety of solid cancers. By microarray analyses, we found upregulated transcriptional MACC1 targets, e.g. SPON2, which by themselves induce metastasis and are prognostic for colorectal cancer (CRC) patients. We analyzed RAS-dependence of MACC1-induced metastasis, supported by our recent finding of improved CRC patient prognosis when combining KRAS13 mutation and MACC1 expression. We also explored the miRNA landscape for MACC1- and S100A4-induced metastasis. We identified MACC1- and S100A4-affecting miRNAs, their epigenetic regulations and evaluated their suitability as markers for metastasis prognostication and patient survival.
We revealed the MACC1 interactome (G. Dittmar, MDC) and phospho-interactome (B. Küster, TU Munich) by mass spectrometry (MS). We found kinases essential for MACC1 Y-phosphorylation, and entire signalosomes of receptor tyrosine kinases as binding partners of pY-MACC1.
We used a human MACC1 promoter reporter system for high throughput screenings (HTS) using the FMP-ChemBioNet (J. von Kries, FMP) and DKFZ/EMBL libraries (N. Gunkel, DKFZ, J. Lewis, EMBL). The human S100A4 promoter reporter system was used for HTS using the NCI/NIH-LOPAC library (R.H. Shoemaker, NCI/NIH Bethesda MD). Thereby we identified the first MACC1 and S100A4 small molecule transcriptional inhibitors.