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Cell death in pancreatic cancer: from pathogenesis to therapy

Abstract

Pancreatic cancer is a devastating gastrointestinal cancer characterized by late diagnosis, limited treatment success and dismal prognosis. Exocrine tumours account for 95% of pancreatic cancers and the most common pathological type is pancreatic ductal adenocarcinoma (PDAC). The occurrence and progression of PDAC involve multiple factors, including internal genetic alterations and external inflammatory stimuli. The biology and therapeutic response of PDAC are further shaped by various forms of regulated cell death, such as apoptosis, necroptosis, ferroptosis, pyroptosis and alkaliptosis. Cell death induced by local or systemic treatments suppresses tumour proliferation, invasion and metastasis. However, unrestricted cell death or tissue damage might result in an inflammation-related immunosuppressive microenvironment, which is conducive to tumour progression or recurrence. The precise extent to which cell death affects PDAC is not yet well described. A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.

Key points

  • The morbidity and mortality of pancreatic cancer continue to increase and constitute a major challenge for basic and applied oncology.

  • Regulated cell death occurs through apoptotic and non-apoptotic pathways, manifesting in different morphological, biochemical and genetic characteristics.

  • Regulated cell death plays a dual role in pancreatic cancer and has been shown to have both pro-tumorigenic and tumour-suppressive effects.

  • Endogenous damage-associated molecular patterns released from stressed, dying or dead cells play a key role in regulating inflammation and immune responses in the pancreatic tumour microenvironment.

  • A concerted preclinical and clinical evaluation is needed to determine whether therapies can induce adequate cell death responses.

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Fig. 1: Core molecular mechanisms of pancreatic cancer cell death.
Fig. 2: Modulation of cell death pathways in pancreatic cancer.
Fig. 3: TP53 in pancreatic cancer cell death.
Fig. 4: Hypoxia in pancreatic cancer cell death.
Fig. 5: Metabolism in pancreatic cancer cell death.
Fig. 6: Autophagy in pancreatic cancer cell death.
Fig. 7: Crosstalk between dying pancreatic cancer cells and immune cells.

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Acknowledgements

We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. G.K. is supported by the Ligue Contre le Cancer (Equipe Labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer; Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), Fondation pour la Recherche Médicale; a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine Program (CARPEM).

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All authors wrote the manuscript. G.K., D.T. and R.K. edited, reviewed and approved the manuscript before submission.

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Correspondence to Rui Kang, Guido Kroemer or Daolin Tang.

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Nature Reviews Gastroenterology & Hepatology thanks H. Jacob, who co-reviewed with A. Saluja; L. Buscail; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Chen, X., Zeh, H.J., Kang, R. et al. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00486-6

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