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 immune-suppressive 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 extra-terminal motif proteins (BETs) 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 mechanism suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease.

Strategies for Increasing Pancreatic Tumor Immunogenicity

“…We and others have demonstrated that low dose cyclophosphamide can also deplete Tregs, modulate the TME and maximize clinical responses to immunotherapy (123,127,128). Another approach is combination therapy with epigenetic modulators, as epigenetic therapy appears to be immunomodulatory (129), and epigenetic therapy in PDAC is reviewed by Evan and colleagues in this CCR focus issue (130). Immunotherapies in clinical development for PDAC in combination with standard chemotherapy include the indoleamine 2,3 dioxygenase (IDO) inhibitor indoximod, the bruton tyrosine kinase (BTK) inhibitor ibrutinib, CD-40 agonists, and CCR2 inhibitors (Table 1).…”

<p>Is there a CDKN2A-centric network in pancreatic ductal adenocarcinoma?</p>

“…73 The abnormal expression of MYC in many cancers, including PDAC, is usually not due to dysfunction of the MYC gene itself, but is caused, for example, by amplification, chromosomal translocation, or upstream carcinogenic signaling disorders, as well as by a loss of tumor suppressor factors. 74,75 MYC is required for the maturation and maintenance of embryonic and adult acinar differentiation, and the activation of MYC signaling induces cancerous changes in pancreatic tissue. 76 MYC overexpression occurs in up to 42% of late PDAC, which is associated with poor clinical outcomes, increased probability of recurrence, worsening disease, and decreased survival in patients with PDAC.…”

Mechanisms of the Antitumor Activity of Low Molecular Weight Heparins in Pancreatic Adenocarcinomas

“…Normal pancreatic tissue has the potential to regenerate after injury in a process involving the activation of stellate cells and fibrosis that isolates the affected area, protects healthy tissue, and resolves after tissue repair. Cancer cells disrupt this regenerative procedure by causing the continuous activation of stellate cells with subsequent excessive stroma production, contributing to tumor growth and disease progression [30]. Invasive pancreatic cancer evolves in a step-wise pattern from precursor lesions, most commonly initiated by pancreatic intraepithelial neoplasia.…”