Abstract A040: Intratumor stem cell repertoire in pancreatic cancer

Abstract

Metastatic pancreatic ductal adenocarcinoma (PDAC) is difficult to manage, has an overall survival of approximately nine months, and will soon be the second leading cause of death among cancers. The poor outcome of PDAC patients has been attributed, in part, to a pattern of intratumor heterogeneity reflected in the genomic heterogeneity as well as the more recently described "lineage heterogeneity". Lineage heterogeneity is assumed from the remarkably divergent histology within each tumor that has been labelled "Classical", "Basal", and "immune classical" or "Intermediate". Metadata related to these apparent lineages suggest clinical relevance as Basal-predominant tumors have a shorter overall survival and appear to be more resistant to chemotherapeutics. To assess a possible stem cell basis for this lineage heterogeneity, we exploit technologies for single stem cell cloning from PDAC ascites. In each case, we identify stem cells committed to Classical, Immune Classical, and Basal subtypes in vitro and in vivo as tumors in immunodeficient mice. Within each patient, these subtype clones share most acquired mutations including KRAS and TP53 alleles, suggesting a post-transformation, epigenetic radiation to distinct tissue types specific to Classical (ca. intestinal mucosa), Immune Classical (ca. gastric mucosa), and Basal (ca. immature stratified mucosa) marked by distinct patterns of tumor microenvironments. Consistently, an epigenetic analysis of these clones supports the activation of gene expression patterns germane to the properties of the respective subtypes. Lastly, these subtype stem cells harbor rigid patterns of susceptibility to chemotherapeutics generalized as Basal<Classical<Immune Classical, with the highly resistant Basal subtype linked to their constitute expression of resistance pathways.