Preclinical developments


Preclinical developments for understanding and intervening in tumor progression and metastasis

 

We established in vivo intervention strategies targeting MACC1 and S100A4 for metastasis inhibition. shRNA acting on MACC1 or S100A4 or on transcriptional or post-translational targets thereof decreased metastasis formation, also when applied systemically. The small molecule transcriptional inhibitors of MACC1 or S100A4, identified by HTS, restricted MACC1- or S100A4-induced metastasis in mice. Thus, we could reposition these already FDA-approved drugs for the new indication of metastasis restriction, paving the way for clinical trials. Based on our MS data, we showed MACC1-induced metastasis restriction in mice when deleting MACC1 pY sites or inhibiting MACC1-phosphorylating kinases using inhibitors already used in clinical trials.

We used PDX models from primary tumors and metastases of colorectal, pancreatic and gastric cancer patients (B. Rau, S. Daum, Charité). We evaluated biomarkers and pathways for progression, metastasis, and response prediction towards conventional and targeted therapies.

We generated the first transgenic MACC1 mouse model (vil-MACC1) and crossed them with ApcMin mice (B. Jerchow, MDC). vil-MACC1/ApcMin mice showed increased number and size of tumors, which possessed an accelerated adenoma-carcinoma-sequence and an invasive phenotype (H. Bläker, Charité) linked to reduced survival times. We found the Wnt and pluripotency signaling increased with upregulation of the pluripotency markers Nanog and Oct4. Nanog and Oct4 are regulated by MACC1 also in cell culture and strongly correlate with MACC1 levels in CRC patients. We provide first evidence that MACC1-induced tumor progression in CRC acts, at least in part, via the newly discovered MACC1/Nanog/Oct4 axis.