Abstract 1715: Whole transcriptome analysis of patient-derived 3D in vitro and xenograft models of colon cancer identifies placental genes required for the survival of cancer stem cells

Abstract

Abstract Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumor growth and the source of relapse following treatment. The identification of genes and pathways required for the survival of CSCs may therefore lead to better treatment outcomes. Here, as part of the OncoTrack* consortium, we report the use of 3D in vitro and xenograft models of patient-derived colon cancer for the identification of novel regulators of CSCs. Increased aldehyde dehydrogenase (ALDH) activity has been demonstrated to be a marker of normal intestinal stem cells and colon CSCs. We therefore isolated and functionally tested ALDH+ cells for CSC properties using 3D in vitro models and xenografts of patient derived colon cancer. These studies revealed ALDH+ cells to be highly enriched for CSCs. In addition, there was a positive correlation between CSC frequency in the models and tumor grade at time of surgical resection. ALDH+ CSCs were subjected to RNA sequencing for whole transcriptome analysis. These analyses demonstrated ALDH+ CSCs to be enriched for stem cell associated genes (ALDH1A1, BMI1, LGR5, CD44, CD166), signaling pathways (Wnt, Hedgehog) and developmental (embryonic, placental, tissue development, EMT) and metabolic processes (retinol metabolism, drug metabolism, hypoxia). Lentivirus mediated gene knockdown was carried out on a panel of genes that were differentially expressed in ALDH+ cells from 3D in vitro models and xenografts. These studies led to the identification of genes required for the self-renewal and survival of colon CSCs. Interestingly, these genes have been reported as important regulators of early embryonic and placental development but have not previously been reported in the regulation of cancer stem cells. *The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement n°115234. Citation Format: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange. Whole transcriptome analysis of patient-derived 3D in vitro and xenograft models of colon cancer identifies placental genes required for the survival of cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1715.