Abstract IA24: Oncogenic Kras and the pancreatic cancer microenvironment

Abstract

Abstract Oncogenic mutations in the KRAS gene are almost invariably associated to pancreatic cancer in humans. Genetic engineered mice that express oncogenic Kras in the pancreas develop pancreatic cancer in a step-wise manner that resembles the progression of the human disease. Invasive cancer is preceded by Pancreatic Intraepithelial Neoplasia (PanIN) formation. In humans and in mice, pancreatic cancer and PanINs are associated to extensive accumulation of fibro-inflammatory stroma. The interactions between epithelial cells and individual components of the stroma, as well as the interaction among components of the stroma are not fully understood. We have recently identified mesenchymal stromal cells (MSCs) as one of the components of the PanIN stroma. MSCs are also present, albeit at lower frequency, in the normal pancreas. Interestingly, PanIN-derived MSCs have increased tumor-promoting ability compared to normal-pancreas-derived MSCs. MSCs have been shown to regulate the recruitment of macrophages in other tumor types. Accordingly, we find that MSCs promote macrophage recruitment in vivo. Moreover, both normal-pancreas derived MSCs and PanIN-derived MSCs promote differentiation of macrophages from bone marrow progenitors in vitro. PanIN-derived MSCs have the unique ability to promote polarization to M2- macrophages. Finally, depletion of macrophages blocks the tumor-promoting effect of MSCs in co-transplantation experiments with pancreatic cancer cells. These preliminary data our data, and previous studies in the literature, provided the rationale for an investigation of the role of monocytes-macrophages in the pancreatic cancer microenvironment. Therefore, we crossed the iKras* mouse model of pancreatic cancer with CD11b-DTR mice that allow depletion of all CD11b+ lineages (monocytes and macrophages) upon administration of Diphtheria Toxin (DT). The iKras* mouse allows inducible and reversible expression of oncogenic Kras. Expression of oncogenic Kras and induction of acute pancreatitis leads to PanIN formation and accumulation of a stroma rich in macrophages. The polarization status of these macrophages is largely M2. Inactivation of oncogenic Kras reverses the accumulation of macrophages, indicating that macrophage infiltration requires signals derived from oncogenic Kras-expressing epithelial cells (directly, or mediated by other cell types within the stroma such as MSCs or fibroblasts). Depletion of macrophages prevents PanIN formation; depletion of macrophages after PanINs have formed leads to their regression. Moreover, macrophage depletion prevents tumor establishment and causes arrest or tumor growth or regression in pre-established transplanted tumors. Thus macrophages emerge as key cell components within the pancreatic cancer stroma. We are currently investigating the mechanism underlying the requirement for macrophages during pancreatic carcinogenesis. Citation Format: Esha Mathew, Yaqing Zhang, Flor Mendez, Fil Bednar, Marina Pasca di Magliano. Oncogenic Kras and the pancreatic cancer microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA24.