DKK3 in pancreatic cancer–Elucidating the roles of a double-edged sword

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-associated mortality in developed countries with a 5-year survival rate of less than 10%. Despite extensive research, there is still a lack of reliable biomarkers for early disease detection and pathophysiology. Therefore, the minute delineation of intimate molecular mechanisms involved in the intratumoral interplay between different compartments of PDAC became of paramount importance. DKK3 (Dickkopf-3), a member of the Dickkopf protein family involved in Wnt signaling, is a rather unique protein: in PDAC, suppression of DKK3 in a Trp53-deficient context negatively impacts tumor progression and prolongs survival. Notably, DKK3 overexpression sensitizes PDAC towards gemcitabine therapy. We previously identified DKK3 as a novel factor for organ regeneration during pancreatitis and, through state-of-the-art investigations involving a set of in vivo models, delineated a direct, previously unknown link between DKK3 and the canonical-Wnt- and Hedgehog-signaling. This, and given that pancreatitis renders as a risk factor for pancreatic cancer, prompted us to investigate the potential role of DKK3 in PDAC development. Our preliminary findings suggest that DKK3 exerts stage, compartment, and even transcript-specific functions during PDAC progression. Intriguingly and challenging at the same time, DKK3 appears to operate either as a "friend" or as a "foe", depending on the spatiotemporal expression during pancreatic carcinogenesis. The current proposal aims at precise characterization of opposing functions of DKK3 during PDAC initiation and progression, and employs cutting-edge in vivo, in vitro, and ex vivo experimental settings at different stages of KRAS-driven tumorigenesis (from early dysplasia to cancer stage). Sophisticated investigations on genetically engineered mice involving time-resolved phenotyping and single-cell transcriptomic sequencing will aid in (i) capturing the minute dynamic of the DKK3 tumor suppressive functions; (ii) reveal ist interference with various signaling cascades over time and (iii) elucidate potential paracrine and autocrine crosstalks between stromal and tumor epithelial compartments. In vitro and ex vivo 3D co-culture experiments involving RNA interference and gene-rescue strategies will further substantiate the compartment and transcript-specific roles of DKK3. At the same time, a versatile ex vivo organ culture platform will enable long-term assessment of both early dysplastic events and tumor progression. Importantly, complex stem cell-derived pancreatic duct-like organoids mimicking tumor-initiating events will not only consolidate, but also translate our findings into a relevant human model. Altogether, the findings of this proposal will provide crucial and essential knowledge about DKK3, a protein featuring a double-edged sword role in carcinogenesis, that rises as a novel genuine biomarker and a promising therapeutic strategy in PDAC.