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PANCREATIC CANCER IN 2020

The war against pancreatic cancer in 2020 — advances on all fronts

Nature Reviews Gastroenterology & Hepatology volume 18, pages 99–100 (2021)Cite this article

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In 2020, important advances were made across three major frontiers of pancreatic ductal adenocarcinoma (PDAC) research: risk factors, therapeutic resistance and tumour recurrence. Pathophysiology of obesity-mediated PDAC initiation was elucidated, novel stromal mechanisms of therapeutic resistance were unveiled and the genetic evolution of recurrent PDAC under therapeutic pressures was tracked in human samples.

Key advances

  • An endocrine–exocrine axis involving cholecystokinin secretion by remodelled β-cells drives obesity-mediated pancreatic ductal adenocarcinoma (PDAC) progression, and this process can be intercepted through weight loss strategies4.

  • Novel avenues for stromal manipulation to improve PDAC therapy were identified in the form of LCCR15+ cancer-associated fibroblasts, which can be used to predict immunotherapy resistance7.

  • Whole-exosome sequencing of primary tumour and matched autopsy samples from patients with recurrent PDAC demonstrated treatment-induced genetic bottlenecks and intermetastatic seeding leading to subclonal heterogeneity in the recurrent tumours, also identifying potentially targetable genetic signatures in recurrent disease9.

Early diagnosis is the ‘holy grail’ of research in the pathogenesis of pancreatic cancer. To this end, efforts have focused on identifying populations at high-risk of PDAC development, understanding mechanisms by which various risk factors lead to pancreatic tumorigenesis and, therefore, developing strategies for primary prevention. Numerous epidemiological studies have linked obesity to an increased risk of PDAC incidence and worse oncological outcomes3; however, the underlying mechanisms remain unclear. Chung et al.4 have now demonstrated that an aberrant endocrine–exocrine signalling axis is the driver of PDAC in the context of obesity. The authors used an elegant KCO mouse model in which KC (Pdx1-Cre; KrasLSL-G12D/WT) mice, which develop spontaneous pancreatic intraductal neoplasia, were crossed with leptin-deficient ob/ob mice, which show early and rapid weight gain4. As expected, accelerated tumorigenesis was observed in the pancreas of KCO mice compared with KC mice. Intriguingly, this increased risk of PDAC development could be intercepted with weight loss by either caloric restriction or leptin administration, albeit only early in the course of the disease4. Interestingly, the authors found that the increased risk of PDAC development was independent of new mutations and was, in fact, driven by a remodelling of the β-cells, leading to an aberrant secretion of the hormone cholecystokinin (CCK)4. Corroborating this hypothesis was the fact that CCK itself was enough to drive pancreatic tumorigenesis in mice in absence of obesity4. The findings of Chung et al. provide important mechanistic insights into obesity-driven PDAC and suggest that obesity drives various transcriptional pathways needed for malignant conversion, not by induction of mutations, but rather by changing the hormonal milieu. The study also offers hope with respect to primary prevention as, at least early in the disease process in mice, this process is reversible, and societal changes might be able to stem the increase in incidence of PDAC.

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Fig. 1: Mechanisms driving pancreatic cancer incidence, recurrence and therapy resistance.

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  1. Division of Surgical Oncology, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA

    Tejeshwar Jain & Vikas Dudeja

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  1. Tejeshwar Jain
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Correspondence to Vikas Dudeja.

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Jain, T., Dudeja, V. The war against pancreatic cancer in 2020 — advances on all fronts. Nat Rev Gastroenterol Hepatol 18, 99–100 (2021). https://doi.org/10.1038/s41575-020-00410-4

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