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Epithelial and stromal co-evolution and complicity in pancreatic cancer

Nature Reviews Cancer volume 23, pages 57–77 (2023)Cite this article

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Abstract

Pancreatic ductal adenocarcinomas are distinguished by their robust desmoplasia, or fibroinflammatory response. Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with or co-opt the surrounding cells and signalling processes in its microenvironment. It is proposed that an invasive pancreatic ductal adenocarcinoma represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose normal tissue composition, architecture and physiology to foster tumorigenesis. The complex kinetics and stepwise development of pancreatic cancer suggests that it is governed by a discrete set of organizing rules and principles, and repeated attempts to target specific components within the microenvironment reveal self-regulating mechanisms of resistance. The histopathological and genetic progression models of the transforming ductal epithelium must therefore be considered together with a programme of stromal progression to create a comprehensive picture of pancreatic cancer evolution. Understanding the underlying organizational logic of the tumour to anticipate and pre-empt the almost inevitable compensatory mechanisms will be essential to eradicate the disease.

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Fig. 1: Epithelial–mesenchymal reciprocity in pancreatic ductal adenocarcinoma.
Fig. 2: Mesenchymal cell lineages and diversity in pancreatic cancer.
Fig. 3: Macrophage lineages in pancreatic cancer.
Fig. 4: Tumour cell–immune cell–cancer-associated fibroblast circuits in pancreatic ductal adenocarcinoma.
Fig. 5: Activation of intracellular mechanisms of force transduction in pancreatic cancer by tensile loading of the collagen network.

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Acknowledgements

The author thanks J. Potter, C. Ghajar and T. Hollingsworth for helpful comments on the manuscript, S. Thorsen for help with preparation of the manuscript, M. Whittle and C. Dufort for help with figure preparation, and a great many colleagues for stimulating discussions. Work in the author’s laboratory is supported in part by NIH/NCI R01 CA161112, R01 CA223483 and U01 CA224193, Cancer Center Support Grant P30 CA015704 and Pancreatic Cancer Action Network Precision Medicine Targeted Grant 17-85-HING.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Medicine, University of Nebraska Medical Center, Omaha, NE, USA

    Sunil R. Hingorani

  2. Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Sunil R. Hingorani

  3. Pancreatic Cancer Center of Excellence, University of Nebraska Medical Center, Omaha, NE, USA

    Sunil R. Hingorani

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Glossary

Acinar-to-ductal metaplasia

(ADM). A postulated transdifferentiation of a mature acinar cell into an abnormal ductal-like cell in response to an oncogenic stimulus with or without a superimposed injury that may give rise to the precursors (pancreatic intraepithelial neoplasias) of pancreatic cancer.

Anlage

A classical term in embryology used to define an area or collection of cells that serve as a foundation, or primordium, for a subsequent developmental event.

Contrast enhancement

The differential uptake of systemically introduced radiographic contrast material by an organ over time or in relation to another adjacent organ.

Ductules

The terminal portions of the branching pancreatic ductal system, which gets progressively smaller in calibre as the tree spreads from the centre of the gland to the periphery.

Elastic modulus

Also called ’Young’s modulus’, a measure of stiffness and formally the slope of the stress–strain curve (that is, a plot of the extent to which a material is reversibly (elastically) deformed in response to an applied force).

Evaginations

Extensions of a sheet of cells while maintaining contiguity to form a protrusion or outpouching from the surface layer (as opposed to invagination, or inward migration of a sheet of cells, to form a dimple or tunnel within a cell mass).

Hedgehog (Hh) signalling

A critical embryonic signalling pathway that figures prominently in the development and differentiation of many tissues and organs of the body and that is regulated by three ligands, Indian Hedgehog (IHH), sonic Hedgehog (SHH) and desert Hedgehog (DHH).

Hexosamine biosynthetic pathway

(HBP). This pathway integrates metabolites from glycolysis with those from amino acid, nucleic acid and lipid breakdown to generate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) for use in critical glycosylation reactions.

Hyaluronan

(HA). A highly soluble, negatively charged, linear unbranched sugar polymer comprising repeating disaccharide units of N-acetylglucosamine (NAG) and d-glucuronic acid that avidly binds water and swells, providing turgor to many tissues in the body.

Myelocytes

Precursors to granulocytes (basophils, neutrophils and eosinophils).

Myelopoiesis

The generation of myeloid (as opposed to lymphoid) cells in the bone marrow, including red blood cells, platelets, mast cells, granulocytes and monocytes (macrophages and dendritic cells).

Nerve plexuses

Confluences or bundles of afferent and efferent nerve fibres from several levels of the spine as they emerge from the foramina.

Non-oxidative pentose pathway

The non-oxidative phase of the pentose phosphate pathway; it generates ribose 5-phosphate for nucleotide synthesis, and this is further metabolized to generate glycolytic intermediates. The oxidative phase generates reducing equivalents in the form of NADPH for reductive biosynthetic reactions.

One-carbon metabolism

A series of elemental reactions built upon folate biochemistry that involve one-carbon molecules (methyl groups) to provide the building blocks for the most fundamental reactions in cellular metabolism.

Pancreaticoduodenectomy

Also called ‘Whipple procedure’ (after its pioneer), a complex surgical procedure involving removal of the head of the pancreas, the adjoining portions (first and second parts) of the small bowel, the extrahepatic biliary ducts and the gall bladder, and previously the pylorus and antrum of the stomach as well, in the attempt to achieve cure of a pancreatic cancer.

Reflux injury

Parenchymal damage in the pancreas caused by forced exudation of digestive enzymes across the ductal barrier because of a downstream obstruction.

Tricarboxylic acid (TCA) cycle

Also called the ‘citric acid cycle’ or the ‘Krebs cycle’, oxidizes acetate (linked to coenzyme A) to generate NADH, which is then used by the electron transport chain in the mitochondria to generate ATP.

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Hingorani, S.R. Epithelial and stromal co-evolution and complicity in pancreatic cancer. Nat Rev Cancer 23, 57–77 (2023). https://doi.org/10.1038/s41568-022-00530-w

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