GENESIS of PDAC: Gene Expression aNd Epigenetic Signatures InStigating Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest
cancers. Two molecular subtypes of PDAC are generally agreed
upon; Classical tumors display typical pancreatic progenitor markers
whereas basal tumors are squamous and have a ΔNp63-signature. A
relationship with normal differentiation states of pancreatic exocrine
cells has not been thoroughly investigated.
Acinar cells dedifferentiate, acquire progenitor markers, undergo
ductal metaplasia and as such can give rise to PDAC with hints of
the classical subtype. Recently, we discovered ΔNp63+ basal cells
among the duct cells that could be of specific relevance in the
ontogeny of the basal PDAC subtype, in analogy with other tissues
where basal tumors originate from ΔNp63+ basal cells.
Here, the transcriptome and the more stable methylome of distinct
differentiation states of human acinar and ductal cells will be
analyzed for unraveling lineage relationships with and between the
PDAC subtypes. Potential gate-keeper genes of tumor and normal
exocrine cell identity will be tested, using organoid cultures. First, we
focus on ΔNp63. Next, we identify and investigate a conserved ‘cell
identity gene’ by including a zebrafish model of acinar cell-derived
PDAC that will additionally serve for genetic manipulation.
This project will add to understanding the origin and evolution of
PDAC subtypes and the potential for therapeutic intervention.