Yordanov, Georgi Nenov (July 2019) Myc and Spdef: two transcription factors hijacked by pancreatic cancer. PhD thesis, Cold Spring Harbor.
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Abstract
Pancreatic cancer is an almost universally lethal disease with a 5-year survival rate of just 9%. While extensive efforts have been focused on defining the genetic alterations that are present in tumors of patients with pancreatic ductal adenocarcinoma (PDAC), less is known about the transcriptional regulatory pathways that promote the progression of the disease. The c-Myc transcription factor features prominently in human cancers, being overexpressed or activated in more than 70% of malignancies. Recent studies, using a genetic dominant negative protein (Omomyc), have demonstrated that Myc inhibition causes rapid eradication of mutant Kras-driven lung adenocarcinomas in vivo. The effects on normal tissue were mild and fully reversible. Similarly, it has been shown that Myc is important for the initiation and progression of PDAC. To address this question, our lab previously generated 3D organoid cultures of pancreatic epithelium and neoplastic tissues from a genetically engineered mouse model (GEMM) of PDAC. Analysis of RNA-seq data comparing normal (WT), pre-neoplastic (KrasG12V) and tumor organoids (KrasG12V; Trp53R172H) showed a clear signature of upregulated Myc target genes in tumor organoids that was not significant when normal organoids were compared to PanIN-derived organoids. However, there was no difference in the mRNA or protein levels of Myc between the normal and tumor organoids. Comparison of Myc occupancy by ChIP-seq revealed a significant overall enrichment of Myc at promoters in tumor organoids. In addition, we identified 841 tumor-specific Myc peaks suggesting differences in the transcriptional regulation by Myc between proliferating normal and tumor cells and propose a model of cooperation between Myc and other transcription factors in PDAC. Additionally, a global transcriptomic comparison of normal duct-derived and tumorderived organoids identified Spdef, an ETS family member, as the most upregulated 17 transcription factor in tumor organoids. Here, we show that Spdef is upregulated in murine tumor organoids in a mutant-Kras dependent manner in vitro and is overexpressed in human PDAC and patient-derived tumor organoids. In tumor organoids, we find that Spdef directly regulates the expression of the GI-specific kinase/endonuclease Ern2/Ire1b. Additionally, Spdef promotes the orthotopic growth of tumor organoids in vivo and the non-canonical splicing of Xbp1 – a central arm of the unfolded protein response pathway. Together, these results reveal a previously unappreciated role of Spdef in pancreatic cancer and nominate its downstream target, Ern2/Ire1b, as a potential therapeutic target for intractable PDAC.
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