Abstract 4895: A cancer stem cell instigator pathway revealed by transcriptomics, stem cell mutagenesis, and in-vivo tumor initiation.

Abstract

Abstract We have developed a multi-stage Cancer Stem Cell (CSC) model that recapitulates the natural process of carcinogenesis. Isogenic human embryonic stem cells (ESCs) exposed to non-biased mutagens were found to undergo rare spontaneous CSC transformation. Progenitor induced CSC (iCSC) clones exhibited classical CSC/SC marker expression, tumorsphere formation, resistance to common chemotherapeutic agents, and a capacity to form serially transplantable tumors in immunocompromised animals. A subset of progenitor clones formed tumors that took on a glioma-like morphology and produced more highly drug resistant mature CSCs that exhibited phenotypic characteristics of the primary patient glioma CSCs. Computational comparison to expression profiles of 313 human tumor lines confirmed that the mature CSCs had adopted a glioma-like expression profile. An integrated molecular model of the instigator pathway was assessed by comprehensive RNASeq transcriptomics, tandem MS proteomics, microRNA profiling, and mutagen-induced molecular polymorphisms. Progenitor iCSCs were found to have an ESC expression phenotype, significantly differing in the expression of only 32 genes, with some bearing direct evidence of mutagenesis in the expressed transcript. The instigator genes formed a proto-oncology seed pathway that was expanded by progressive expression changes to a more classical oncology profile in the glioma-like tumors and mature iCSCs derived in vivo from the progenitor iCSC. Classical oncology targets evident in the late-stage tumor model were absent in the progenitor iCSCs. However, computational repositioning analysis identified a limited set of existing molecules that could act directly to mitigate the progenitor pathway in the iCSCs. Citation Format: Ana Krtolica, Jacob Glanville, Gnanaratnam Giritharan, Eduardo Caceres, Erica Canino, Kyung-Ah Kim. A cancer stem cell instigator pathway revealed by transcriptomics, stem cell mutagenesis, and in-vivo tumor initiation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4895. doi:10.1158/1538-7445.AM2013-4895