Sub-classification and oncogenic network analysis of ALDH1A3-positive pancreatic ductal adenocarcinoma

• Applicant: Privatdozent Bo Kong, Ph.D.
• Subject Area: Gastroenterology ; Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438480199

Pancreatic ductal adenocarcinoma (PDAC) is a histopathologically defined tumor entity with devastating prognosis. A number of clinically relevant molecular subtypes have already been identified. One squamous subtype also known as quasi-mesenchymal subtype (QM-PDA) contributes particularly to the dismal mortality rates of PDAC. However, the clinical outcome of squamous (QM-PDA) subtype is still heterogeneous and subtyping of squamous (QM-PDA) subtype is necessary to offer more concise patient stratification. Using a reverse-translational approach, we previously defined a highly aggressive PDAC subtype labeled by ALDH1A3 (aldehyde dehydrogenase 1 family member A3) expression. Furthermore, ALDH1A3-positive PDAC was found to be partially overlapping with a previously defined squamous (QM-PDA) subtype. Application of 2-mean clustering for ALDH1A3 expression across microarray datasets for cell lines, patient-derived xenograft (PDX), and micro-dissected tumor tissues identified eight subtype-specific markers. Based on dynamic transcriptional data generated from a small-scale lentiviral shRNA library, we constructed an oncogenic network from these eight markers. Our analysis revealed that this specific network was AP-1 (activator protein-1) dependent and the expressing predominant subunit of AP-1 could potentially be used to sub-classify ALDH1A3-positive PDAC. In vivo functional characterization and network dynamics under different targeted pharmaceutical inhibition have identified a combinational therapy of triptolide and paclitaxel that dramatically inactivated AP-1 activity in vitro and eliminated ALDH1A3-positive PDAC in vivo. In this proposal, we aim to further investigate the molecular mechanism responsible for the synergistic effect of paclitaxel and triptolide on AP-1 inhibition. Furthermore, this combinational therapy will be further tested in a number of preclinical platforms including in vitro high-throughput automatic cytostatic screening and PDXs models.

• DFG Programme: Research Grants