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Emerging role of microRNAs to tackle drug resistance in pancreatic cancer
  1. Albrecht Neesse1,
  2. Thomas M Gress2
  1. 1 Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Georg August University Goettingen, Goettingen, Germany
  2. 2 Department of Gastroenterology, Endocrinology, Infectiology and Metabolism, Philipps-University, Marburg, Germany
  1. Correspondence to Dr Albrecht Neesse, Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Robert Koch Str. 40, Goettingen 37075, Germany; albrecht.neesse{at}med.uni-goettingen.de

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Despite the recent emergence of novel chemotherapy regimen such as nab-paclitaxel/gemcitabine and FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin), pancreatic ductal adenocarcinoma (PDA) is characterised by a poor response to chemotherapy and radiotherapy. Therefore, it remains a challenge for clinicians and scientists likewise to overcome resistance to treatment. PDA silently develops from preneoplastic lesions (PanINs I–III) to invasive cancer over a long period of time. A number of genetic mutations have been identified and well characterised during the evolution of PDA, such as the Kras oncogene, and tumour suppressor genes p16, p53 and DPC4. In addition to genetic mutations, epigenetic modifications and complex alterations within the tumour microenvironment give rise to cell autonomous and non-cell autonomous mechanisms of therapy resistance. Over the past years, it has emerged that therapeutic resistance is, at least in part, mediated by cancer stem cells (CSCs) that are perpetuated within a small fraction of cells within the tumour bulk.1 Stemness and epithelial to mesenchymal transition are closely related on a molecular level and have both been associated with therapeutic resistance in several solid tumours.2 However, mechanisms of chemoresistance in (pancreatic) CSCs that could be exploited for the design of future therapies in highly treatment-resistant cancers are only starting to evolve.

MicroRNAs (miRNAs) are a large family of RNAs that are evolutionarily widespread and highly conserved regulatory, non-coding RNA molecules of about 22 nucleotides in length. miRNAs play pivotal roles in controlling and regulating gene expression during maintenance of biological homeostasis and diseases such as cancer. In this issue of Gut, Cioffi et al 3 identify the miR-17-92 family in pancreatic cancer to mediate stemness and chemoresistance in a distinct subpopulation of pancreatic cancer cells. The authors employ anchorage-independent cultures and gemcitabine treatment sequentially to enrich for CSCs in vitro. In vivo, corresponding patient-derived xenografts (PDXs) treated with chemotherapy are used to gain CSCs. In both approaches, the authors isolate a slow-cycling/quiescent, highly chemoresistant subpopulation of CSCs. Subsequent miRNA expression profiling revealed that both gemcitabine-treated PDXs (compared with vehicle treatment) and sphere-derived CSCs (compared with adherent CSCs) showed downregulation of the miR-17-92 cluster. In a set of elegant and well-executed loss of function and gain of functions experiments, the authors demonstrate both in vitro and in vivo that the miR-17-92 cluster negatively controls CSC features such as enhanced tumourigenicity, sphere formation, metastatic activity and response to several relevant chemotherapies. Mechanistically, several target genes of miR-17-92 are identified that are linked to the activated Nodal/Activin/TGF-β signalling pathway and had been previously associated with stemness features. Furthermore, the miR-17-92 cluster is shown to regulate and control CSC features via targeting of ALK4, p21 and the transcription factor T-box 3. Taken together, these results illustrate the molecular complexity of a highly tumourigenic and treatment-resistant subpopulation of pancreatic cancer cells within the tumour bulk that is mediated by the downregulation of miRNAs, particularly the miR-17-92 family. In a wider sense, this work exemplifies that chemoresistance is a multifaceted matter involving both genetic and epigenetic alterations. In PDA, pronounced changes within the tumour microenvironment with immune and stromal cell interactions add another layer of complexity that promote stemness and chemoresistance and make pancreatic cancer so intractable. In the same issue of Gut, the Heeschen group provide compelling evidence that a previously unrecognised immunomodulatory cationic antimicrobial peptide 18/LL-37 (hCAP-18/LL-37) that is secreted by immune cells of the pancreatic tumour stroma is crucial for pancreatic CSC-mediated tumourigenesis.4 The molecular interactions between activated fibroblasts and immune cells with pancreatic tumour cells in the tumour microenvironment is certainly a hot topic in the pancreas cancer field with potential translational and clinical implications. Recently, pharmacological and genetic depletion of activated fibroblasts were shown to result in accelerated pancreatic tumour growth, increased invasiveness, stemness and immune modulation in several genetically engineered mouse models of pancreatic cancer.5 ,6 These data have cast doubts on the therapeutic concept of stromal depletion as a successful approach to tackle pancreatic cancer. However, such stroma-modifying therapies may also open therapeutic windows for immunological checkpoint antagonists (eg, programmed death ligand-1 and cytotoxic T-lymphocyte-associated protein 4 antibodies) or vascular endothelial growth factor antibodies that otherwise fail in patients with PDA.5 ,6 Therefore, stromal and transcriptional reprogramming is currently pursued as one potentially successful strategy to overcome therapy resistance.7–9

To conclude, miRNAs are certainly a promising and emerging target to tackle mechanisms of chemoresistance in PDA. Several miRNA antagonists and miRNA mimics are currently being developed for preclinical and clinical applications in various diseases. However, the poor pharmacokinetic properties of miRNAs as well as unspecific binding remain major obstacles for the successful clinical translation. As an alternative, epigenetic drugs could prove successful to modify miRNA expression. Recent preclinical work has provided evidence that systematic screening approaches are able to select effective histone deacetylase (HDAC) inhibitors to restore miRNA-mediated drug resistance. To this end, the class I HDAC inhibitor mocetinostat was shown to interfere with ZEB1 function, restore miR-203 expression and induce chemosensitivity in PDA.10

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Footnotes

  • Contributors AN wrote the commentary. TMG critically revised and corrected the manuscript.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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