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PANCREATIC CANCER

Pancreatic cancer: why the cell of origin matters

Nature Reviews Gastroenterology & Hepatology volume 19, page 279 (2022)Cite this article

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The cell of origin of pancreatic cancer has long been controversial. Historically, histological similarity suggested ductal cells, as reflected in the term ‘ductal adenocarcinoma’, as the cell of origin. This view has been questioned by elegant cell lineage-tracing experiments identifying acinar cells as the origin. Is this merely an academic question? Studies published in the past few years by Flowers et al., Neuhöfer et al. and Müller et al. draw a different conclusion: the cell of origin not only influences the molecular cancer subtype, but also predicts aggressiveness and survival.

Previously it was shown that a tumorigenic KRAS mutation in acinar cells induces age-dependent metastasized pancreatic ductal adenocarcinoma (PDAC) with a classical subtype. Müller and colleagues showed that increased oncogenic dosage variations in KRAS drives both early tumorigenesis and metastasis, which explains early PDAC dissemination in humans. Flowers et al. showed that an additional TP53 mutation speeds up carcinogenesis. In ductal cells, the additional TP53 mutation is critically required for PDAC development: the time until a fully established basal-like subtype tumour is detected is longer than in acinar cell-derived carcinogenesis, but overall survival is substantially shorter. We are dealing with two different tumours and, in the era of precision medicine, this will influence treatment options.

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References

Original article

  • Flowers, B. M. et al. Cell of origin influences pancreatic cancer subtype. Cancer Discov. 11, 660–677 (2021)

    Article  CAS  Google Scholar 

Related articles

  • Neuhöfer, P. et al. Acinar cell clonal expansion in pancreas homeostasis and carcinogenesis. Nature 597, 715–719 (2021)

    Article  Google Scholar 

  • Müller, S. et al. Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature 554, 62–68 (2018)

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine II, LMU hospital, Munich, Germany

    Julia Mayerle

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  1. Julia Mayerle
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Correspondence to Julia Mayerle.

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The author declares no competing interests.

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Mayerle, J. Pancreatic cancer: why the cell of origin matters. Nat Rev Gastroenterol Hepatol 19, 279 (2022). https://doi.org/10.1038/s41575-022-00595-w

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