Abstract
Simple SummaryPancreatic cancer is one of the hardest-to-treat cancers. This is mainly due to its heterogeneity, where subsets of cancer cells possess distinct properties and abilities that determine if and how they metastasize or respond to therapy. DNA barcoding technologies have emerged as a powerful tool to study this heterogeneity, as they allow labeling of individual tumor cells within a cancer cell pool and follow their cellular states and fates during metastasis or upon therapy. The aim of this review was to provide an overview of the various levels of tumor heterogeneity in pancreatic cancer, the obstacles these levels of heterogeneity can cause for effective personalized treatment strategies, and how different barcoding approaches can be applied to study these important questions.Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.
Highlights
Even though the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) has recently reached double-digit numbers at 10.8% [1], it still remains undoubtedly one of the deadliest human malignancies with an extremely poor prognosis
This requires an in-depth understanding of theclonal dynamics and the evolution of cellular populations that give rise to all levels of tumor heterogeneity
Inter-Tumor Heterogeneity PDAC is a unique type of tumor, characterized by its high heterogeneity and a very rich desmoplastic stroma, which can make up to 90% of the tumor volume
Summary
Even though the 5-year survival rate of pancreatic ductal adenocarcinoma (PDAC) has recently reached double-digit numbers at 10.8% [1], it still remains undoubtedly one of the deadliest human malignancies with an extremely poor prognosis. The fact that only a subset of patients who develop a rash as a side effect benefit from erlotinib treatment already emphasizes an underlying heterogeneity in PDAC biology, indicating an urgent need for a more individualized treatment structure and stratifying biomarkers This requires an in-depth understanding of the (sub-)clonal dynamics and the evolution of cellular populations that give rise to all levels of tumor heterogeneity. Single cell RNA sequencing from PDAC patients’ biopsies showed high inter-tumor heterogeneity between patients within the cancer cells, with stromal cells being more homogenous [10] This type of heterogeneity is mostly recognized as an underlying cause for symptoms in different patients, predisposition to early metastasis, and sensitivity to treatment
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