Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked

Abstract

The "hallmarks" of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive, and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix, and immune cells. The oncogenically activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immunosuppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue-specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity, and maintenance. Hence, interfering with such super enhancer-driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extraterminal motif proteins, have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanisms suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease. Clin Cancer Res; 23(7); 1647-55. ©2017 AACRSee all articles in this CCR Focus section, "Pancreatic Cancer: Challenge and Inspiration."

Figure 1. A simplified view of typical enhancers versus super enhancers

Enhancers are orientation and position-independent cis-acting regulatory elements distally located from transcription start sites (TSS). Enhancers are typically bound by multiple transcription factors to regulate gene expression outcomes. Regions of chromatin incorporating multiple enhancers, defined by ChIP-Seq (e.g. H3K27Ac, Med1, BRD4) within 12.5 kb, are referred to as super enhancers. Super enhancers are typically an order of magnitude larger than typical enhancers in size, have higher transcription factor density and greater ability for transcriptional activation.

Figure 2. Oncogenes driving pancreatic cancer hack the endogenous pancreas regenerative program

The regeneration of damaged pancreas requires the coordinated and interdependent activities of multiple cell lineages to rebuild the characteristic structure and function of the damaged tissue. We posit that cell-specific super enhancer networks are integrated into a carefully choreographed whole through continuous exchange of signals (shown much simplified). Both the super enhancer networks and the signals that integrate them offer novel targets for therapeutic intervention.

Figure 3. Super enhancers can be altered in a cancer-type specific manner

The same gene can be regulated by cancer-type specific super enhancers in different cell types to promote malignancy. Transcriptional activation of oncogenic genes can be modulated by the activities of super enhancers, which can be gained as a consequence of extracellular signals, genomic rearrangements, as well as genomic locus and focal amplifications.

Figure 4. Putative therapeutic interventions directly or indirectly target super enhancers and epigenetic networks in multiple cell lineages in pancreatic regenerative program

A range of novel drugs (shown in red) directly or indirectly disrupt super enhancers by targeting epigenetic modifiers that integrate the regenerative super enhancer-driven sub-programs in each of the epithelial and stromal compartments that participate in the hacked repair program.