Abstract
Effective treatments for pancreatic ductal adenocarcinoma (PDAC) are lacking, and targeted agents have demonstrated limited efficacy. It has been speculated that a rare population of cancer stem cells (CSCs) drives growth, therapy resistance, and rapid metastatic progression in PDAC. These CSCs demonstrate high clonogenicity invitro and tumorigenic potential invivo. However, their relevance in established PDAC tissue has not been determined. Here, we use marker-independent stochastic clonal labeling, combined with quantitative modeling of tumor expansion, to uncover PDAC tissue growth dynamics. We find that in contrast to the CSC model, all PDAC cells display clonogenic potential in situ. Furthermore, the proximity to activated cancer-associated fibroblasts determines tumor cell clonogenicity. This means that the microenvironment is dominant in defining the clonogenic activity of PDAC cells. Indeed, manipulating the stroma by Hedgehog pathway inhibition alters the tumor growth mode, revealing that tumor-stroma crosstalk shapes tumor growth dynamics and clonal architecture.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) originates from the exocrine compartment of the pancreas and is the most common type of pancreatic cancer
It is commonly thought that a small subset of tumor cells, the pancreatic cancer stem cells (CSCs), are responsible for tumor growth, invasion, metastasis, and recurrence (Abel and Simeone, 2013; Hermann et al, 2007; Li et al, 2007; Makohon-Moore and Iacobuzio-Donahue, 2016)
With the exception of CD133, most of these CSC markers are expressed in PDAC but their levels increase during progression from pancreatic intraepithelial neoplasia (PanIN) to carcinoma (Kure et al, 2012)
Summary
Pancreatic ductal adenocarcinoma (PDAC) originates from the exocrine compartment of the pancreas and is the most common type of pancreatic cancer. A widely used method to study CSCs is by the identification of this subpopulation using cell-surface markers in primary cancers or experimental models. These populations show enrichment for tumorigenic potential following transplantation in immune compromised mice or by clonogenic assays in vitro. A disadvantage of these techniques is that only the marker-expressing cells are examined for their clonogenic potential and that the unmarked cells remain untested This is of particular relevance as non-marker expressing populations might acquire a CSC phenotype and functionality at another moment during tumor growth.
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