Abstract 3168: A role for tumor-derived CCL2 in directing leukocyte infiltration and stromal heterogeneity in pancreatic ductal adenocarcinoma

Abstract

Abstract Tumor heterogeneity within solid tumors is a recognized barrier to the efficacy of standard therapies. In pancreatic ductal adenocarcinoma (PDAC) the microenvironment is characterized by varying degrees of cytokine/chemokine production, stromal extracellular matrix, and immune cell infiltrates (Hezel et al. 2006). To investigate stromal phenotypical differences in PDAC, we have used the KrasG12D-; Trp53R172H; Pdx-1 Cre (KPC) genetically engineered mouse model which recapitulates tumor heterogeneity seen in human PDAC (Hingorani et al. 2005). Gross histological analysis of KPC tumors allowed us to stratify tumors into 2 broad groups: stromal and non-stromal. We found that stromal tumors were comprised of a significant macrophage infiltrate, whereas non-stromal tumors were generally void of macrophages. We modeled this stromal heterogeneity using tumor cell lines derived from KPC tumors. We found that, when implanted under the skin of wild-type mice, some cell lines produced stromal tumors rich in macrophages, while others formed non-stromal tumors with few macrophages within the microenvironment. Supernatant cultured from these KPC tumor cell lines in vitro revealed elevated CCL2 production, specifically in cell lines from stromal tumors. As CCL2 is a known chemo-attractant for monocytes, we hypothesized that tumor-derived CCL2 contributes to monocyte recruitment and stromal heterogeneity within the tumor microenvironment. To test this hypothesis, we have used an in vitro trans-well migration assay. With this assay, we found that more bone marrow derived cells migrate toward supernatant from stromal tumors relative to non-stromal tumors. This finding was lost in the presence of a CCL2 inhibitor. Ongoing studies are examining a role for tumor-derived CCL2 in regulating tumor-associated stroma in PDAC. Our findings suggest the importance of tumor-immune cell interactions in defining stromal heterogeneity and may offer insight into mechanisms that regulate the stromal compartment in human PDAC. Citation Format: Graham M. Tooker, Whitney L. Gladney, Gregory Beatty. A role for tumor-derived CCL2 in directing leukocyte infiltration and stromal heterogeneity in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3168. doi:10.1158/1538-7445.AM2015-3168