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Correspondence to Dr Kathleen E DelGiorno, Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37212, USA; [email protected] ; Dr Oren Parnas, Lautenberg Center for Immunology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; [email protected]
Key messages
The exocrine pancreas has more epithelial heterogeneity under homoeostatic conditions than previously appreciated.
Pancreatic acinar cells demonstrate a remarkable level of plasticity under conditions of injury or oncogenesis and can transdifferentiate to cell types which direct disease progression.
Single-cell RNA sequencing (scRNA-seq) of murine models identifies epithelial and stromal changes along the metaplasia to preneoplasia to cancer transition.
Fibroblast taxonomy has rapidly expanded and may reflect new cell types or interconvertible states that modulate and/or reflect disease progression.
Tumourigenesis is accompanied by the replacement of a proinflammatory milieu with an immune suppressive infiltrate dominated by myeloid-derived suppressor cells and exhausted T cells.
scRNA-seq and spatial profiling of naïve and chemotherapy-treated patient samples identifies potential mechanisms of resistance and targetable states.
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is currently the third-leading cause of cancer-related deaths in the USA. PDAC has an abysmal 5-year survival rate of only 11% due to late diagnosis and an exceptional recalcitrance to therapy.1 These statistics demonstrate that a greater understanding of pancreas biology and disease progression is desperately needed to better treat patients. While PDAC is typically detected at a locally advanced or distant metastatic stage, microscopic lesions, including pancreatic intraepithelial neoplasia (PanINs) and cysts such as intraductal papillary mucinous neoplasms (IPMNs), are formed several years before cancer detection; the epithelial cells that associate with these lesions are suspected to transform and become cancerous. Constitutively, active mutant KRAS is a major driver of PDAC and is often expressed in cells that comprise premalignant lesions, affecting the epithelial cells themselves and their interactions with other cells in the tissue. Environmental signals (eg, diet, smoking and alcohol) or idiopathic stimuli can induce pancreatitis, an inflammatory condition of the pancreas. Acute pancreatitis is common and is a leading cause of gastrointestinal (GI)-related hospitalisations. Acute pancreatitis ranges from mild to severe, with high morbidity and mortality, however, few treatments exist.2 In its chronic form, pancreatitis is a risk factor for PDAC.3
Although neoplastic cellularity can vary within and between tumours, on average,...