Abstract 3106: Collagen-mediated chromatin remodeling promotes chemoresistance in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related deaths in the US, is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells grown in the collagen microenvironment are resistant to gemcitabine-induced proliferation- and checkpoint-arrest (Dangi-Garimella et al, Cancer Research 2011). The effects were mediated by ERK1/2-dependent expression of high mobility group A2 (HMGA2), a well-known chromatin remodeling protein. We have now found that relative to cells grown on tissue culture plastic, PDAC cells grown in 3D collagen display increased acetylation of lysines K9 and K27 on histone H3 along with a reduction in the levels of the heterochromatin binding protein HP1-α, suggesting that cells in collagen have a more open chromatin state. Decreasing HMGA2 expression or inhibiting ERK1/2 activity attenuates the effect of collagen on K9 and K27 acetylation. 3D collagen also promotes expression of the histone acetyl transferase (HAT) enzymes PCAF and GCN5 through increased HMGA2 expression and ERK1/2 activation. Additionally, human PDAC tumors display higher histone acetylation near fibrotic regions that also have increased HMGA2 expression. Finally, cells in 3D matrix demonstrate increased H2AX and a reduced tailing with the comet assay following gemcitabine treatment, suggesting that there is increased DNA repair associated with the more open chromatin state when cells are in the 3D collagen microenvironment. Downregulation of HATs along with inhibition of ERK1/2 phosphorylation attenuates gemcitabine-induced H2AX detected in 3D collagen. Overall, our results increase our understanding of how growth in 3D collagen contributes to chemo-resistance and identify potential therapeutic targets against this deadly cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3106. doi:1538-7445.AM2012-3106