Characterization of tumour initiating cells in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a poor prognosis and limited response to therapy, much due to the significant heterogeneity within tumours. The tetraspanin CD9 was recently identified as a marker of PDAC tumour-initiating cells (TICs).

CD9high PDAC cells was shown to be required and sufficient for generating PDAC cellular heterogeneity, suggesting that the cellular diversity of PDAC is formed through differentiation of TICs. The proposed project aims to elucidate the function and molecular pathways controlling CD9high cells. Using genetically engineered mice, we will isolate PDAC cells and subsequently sort CD9high and CD9low cells.

RNAseq will determine their transcriptional profile and allow us to identify genes that are differently regulated between the two cell types.

The functional role of the genes will be investigated using a number of molecular approaches, including gene silencing, colony-formation assays, and in vivo xenograft studies.

Additionally, we will use human PDAC organoids to fully characterize the role of these genes in tumour initiation, growth and survival.

Overexpression and CRISPR-mediated knockout of genes will allow investigation of protein-protein interactions, localization, and the catalytic activities of the identified TIC-associated genes.

This work will unravel the role of TICs in PDAC maintenance and heterogeneity and break new ground by elucidating fundamental mechanisms governing PDAC biology.