In this video we discuss how pancreatic stellate cells (PSCs) represent a key component of tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) and contribute to drug resistance. Moreober we explain that c-MET receptor tyrosine kinase activation plays an important role in tumorigenesis in different cancers including PDAC. Effects of PSC conditioned medium (PCM) on c-MET phosphorylation (by immunocytochemistry enzyme-linked immunosorbent assay (ELISA)) and drug response (by sulforhodamine B assay) were investigated in five primary PDAC cells. In novel 3D-spheroid co-cultures of cyan fluorescence protein (CFP)-firefly luciferase (Fluc)-expressing primary human PDAC cells and green fluorescence protein (GFP)-expressing immortalized PSCs, PDAC cell growth and chemosensitivity were examined by luciferase assay, while spheroids’ architecture was evaluated by confocal microscopy. PCM of cells pre-incubated with PDAC conditioned medium, containing increased hepatocyte growth factor (HGF) levels, made PDAC cells significantly more resistant to gemcitabine, but not to c-MET inhibitors. Hetero-spheroids containing both PSCs and PDAC cells were more resistant to gemcitabine compared to homo-spheroids. However, c-MET inhibitors (tivantinib, PHA-665752 and crizotinib) were equally effective in both spheroid models. In conclusion, we developed spheroid models to evaluate PSC-PDAC reciprocal interaction, unraveling c-MET inhibition as an important therapeutic option against drug resistant PDAC.
This video has been published as supplemental file to the article:
Cancers (Basel). 2019 May 8;11(5). pii: E638. doi: 10.3390/cancers11050638
Role of c-MET Inhibitors in Overcoming Drug Resistance in Spheroid Models of Primary Human Pancreatic Cancer and Stellate Cells
Firuzi O, Che PP, El Hassouni B, Buijs M, Coppola S, Löhr M, Funel N, Heuchel R, Carnevale I, Schmidt T, Mantini G, Avan A, Saso L, Peters GJ, Giovannetti E.
Of note, the author of this paper, Professor Omidreza Firuzi (from the Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz, Iran), won the NWO Visitor’s Travel grant to work for one year in our lab.