Abstract A68: Oncogenic Kras prevents myeloid cell-mediated pancreatic tissue repair

The iKras* mouse model of pancreatic cancer allows inducible and reversible expression of oncogenic Kras, and is thus perfectly suited to determine the role of Kras at different stages of carcinogenesis. KRAS has emerged as a targeted interest for study by the NCI; elucidating Kras-dependent signaling pathways and understanding the role of epithelial cells harboring oncogenic Kras in modulating essential components of the tumor microenvironment will provide new opportunities to attack KRAS driven cancers.Using this model, we have demonstrated that, in addition to epithelial changes, the accumulation of a fibro-inflammatory stroma is continuously dependent on oncogenic Kras. Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesion to pancreatic cancer, is characterized by the accumulation of a fibro-inflammatory stroma rich in myeloid cell infiltrates. Here, we generated p48Cre; TetO-KrasG12D; Rosa26rtTa-IRES-EGFP; CD11b-diphtheria toxin (DT) receptor (iKras*;CD11b-DTR) mice that allow us to deplete myeloid cells during the onset and progression of PanINs. We show that myelois infiltration and polarization is dependent on oncogenic Kras both during the initiation and the progression of PanINs. Furthermore, signals derived from oncogenic Kras–expressing cells regulate the polarization of myeloid cells, maintaining them in a pro-tumor status. We show that myeloid cells are required for the initiation and progression of pancreatic cancer precursor lesions by regulatin...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Early Detection Source Type: research