Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Abdel Nasser Hosein, Huocong Huang, Zhaoning Wang, Kamalpreet Parmar, Wenting Du, Jonathan Huang, Anirban Maitra, Eric N Olson, Udit Verma, Rolf A Brekken

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4 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death, with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression, a highly complex and dynamic process, featuring changes in cancer cells and stromal cells. A comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression. To that end, we used single-cell RNA-sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models. Our data indicate that an epithelialmesenchymal transition of cancer cells accompanies tumor progression in addition to distinct populations of macrophages with increasing inflammatory features. We also noted the existence of 3 distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to 2 distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumor fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts may be dynamically regulated by epigenetic mechanisms. This study systematically describes the landscape of cellular heterogeneity during the progression of PDA and has the potential to act as a resource in the development of therapeutic strategies against specific cell populations of the disease.

Original languageEnglish (US)
Article numbere129212
JournalJCI Insight
Volume4
Issue number16
DOIs
StatePublished - Jul 23 2019

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ASJC Scopus subject areas

  • Medicine(all)

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