Pancreatic Ductal Adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer, accounting for 90% of patient cases. PDAC originates from the exocrine gland and develops through preneoplastic lesions that are formed in regenerative response to inflammatory insults or due to oncogenic KRAS activation. Multiple studies demonstrated that activating KRAS mutations such as KrasG12D or KrasG12V are necessary for PDAC formation, but not sufficient to drive its further development. Besides oncogenic KRAS activation, there are a few frequent mutations occurring in PDAC concerning CDKN2A inactivation (encoding for the tumor suppressors p16INK4a and p19ARF), TP53 mutation potentially leading to gain-of-function of the respective p53 protein, and loss of deleted in pancreatic carcinoma, locus 4 (DPC4), also known as SMAD4. However, the genetic heterogeneity of PDAC is created by low frequency genetic alterations that can influence the communication of malignant cells with a variety of normal untransformed cells in the tumor stroma.
The pancreatic tumor stroma comprises cellular and acellular components. Various cell types like cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells are essential untransformed participants in the tumor microenvironment. Stromal cells such as CAFs and myeloid cells secrete vast amounts of extracellular matrix components like collagens and hyaluronic acid that contribute to disease progression. The establishment of tumor microenvironment is vastly driven by malignant cells recruiting peripheral nonmalignant cells through paracrine signaling and reprogramming them to form a growth-promoting niche.
I am specifically interested in:
- How environmental cues trigger signal transduction within malignant tumor cells
- How malignant cells attract specific stromal cell subtypes and reprogram them
- How inhibition of malignant cell-derived paracrine factors changes the composition of the tumor microenvironment