Abstract 4135: A polyclonal origin for pancreatic cancer metastases

Abstract

Abstract Cancer genome studies demonstrate that tumors are comprised of multiple sub-clones with varied genetic and phenotypic properties. Metastases are often depicted as arising from these subpopulations through seeding by single cells, leading to clonally-derived lesions at distant sites. Alternatively, it has been suggested that metastases can also arise from the collective migration of tumor cells, resulting in formation of polyclonal metastases. To better understand the dynamics of metastasis formation in native tumors, we employed the multi-color “Confetti” lineage tracing system, in an autochthonous mouse model of pancreatic ductal adenocarcinoma (PDAC). Through the stochastic expression of distinct fluorescent proteins in any given cell, we tracked the contribution of different tumor subpopulations to malignant progression. We find that early pre-malignant lesions exhibit significant clonal heterogeneity but this clonal diversity decreases during progression to frank carcinoma. Furthermore our data provide the first direct evidence for polyclonal metastasis in the context of a naturally-evolving tumor and suggest that seeding and colonization of metastatic sites involves interactions between at least two distinct tumor populations. We also observe that clonal evolution during metastatic growth varies significantly between the sites of metastatic invasion, resulting in either monoclonal or polyclonal outgrowth. These results provide and unprecedented window into the dynamic changes in clonality that accompany tumor progression and suggest that heterotypic interactions between tumor subpopulations and microenvironmental factors unique to each tissue site contribute to the clonal evolution of metastases. Citation Format: Ravikanth Maddipati, Ben Z. Stanger. A polyclonal origin for pancreatic cancer metastases. [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 4135. doi:10.1158/1538-7445.AM2015-4135