Abstract 2913: Transcriptional reprogramming of pancreatic stroma induces metabolic changes in pancreatic tumor cells

Abstract

Pancreatic cancer remains one of the most lethal of all solid tumors largely due to an aggressive stroma that constitutes the bulk of the tumor. The notion of a reprogrammed stroma suggests the re-establishment of a physiologically normal tumor microenvironment with quiescent stellate cells and fibroblasts. The induction of a quiescent phenotype hinders the aberrant tumor-stroma crosstalk and enables the increased intratumoral delivery of chemo drugs. A combinatorial transcriptional therapy has proven successful at normalizing the tumor microenvironment by reverting the activated state of stromal cells back to quiescence, both at the phenotypic and genetic levels. Indeed, we have observed a reduction in the activation markers of primary human stellate cells and fibroblasts, accompanied by an increase in the quiescence markers. Observations from methylation/hydroxymethylation profiling and metabolic rewiring through isotopomer flux analysis revealed potential targets for therapeutic intervention. In addition, the differential metabolic rewiring induced by a quiescent stroma in cancer cells suggests a tumor suppressive environment aimed at weakening an otherwise aggressive cancer. Citation Format: Joelle Baddour, Lifeng Yang, Abhinav Achreja, Seth Padmabandu, Pari Shah, Rebecca N. Curtis, Thomas Plackemeier, Radina Khalid, Juan C. Marini, Janusz Franco-Barraza, Edna Cukierman, Chaoxin Hu, Anirban Maitra, Deepak Nagrath. Transcriptional reprogramming of pancreatic stroma induces metabolic changes in pancreatic tumor cells. [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 2913. doi:10.1158/1538-7445.AM2015-2913