Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

Abstract

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.

Reviewing the progress of cancer research in the USA

“…Genomic research has shed light on the inherent heterogeneity within cancers, recognizing that tumors from different individuals or even within the same patient can harbor distinct genetic profiles. This understanding of intra-tumor and inter-tumor heterogeneity has profound implications for treatment strategies, emphasizing the need for personalized approaches tailored to the unique genetic makeup of each patient's cancer (Dujardin et al, 2021).…”

The continuing evolution of barcode applications: Functional toxicology to cell lineage

“…Cancer cells exhibit accelerated genetic instability, and it is unclear whether resulting mutations can drive growth or are merely spectators. 80 These strategies are now being implemented to guide clinicians in treatment of advanced stage pancreatic cancer 81 and head and neck cancers. 82…”

“…Cancer cells exhibit accelerated genetic instability, and it is unclear whether resulting mutations can drive growth or are merely spectators. 80 These strategies are now being implemented to guide clinicians in treatment of advanced stage pancreatic cancer 81 and head and neck cancers. 82 The basic scheme to address the question is to use CRISPR/CAS9 to introduce both silent mutations and known mutations into the cancer cells and then trace which cells become more proliferative.…”

Best Practices in Designing, Sequencing, and Identifying Random DNA Barcodes

“…Until recently, tracking cell lineages was a slow and labor-intensive process (Conklin 1905 ; Serbedzija et al 1989 ; Holland and Varmus 1998 ; Kretzschmar and Watt 2012 ; Hsu 2015 ). Recent advances in genetic engineering and nucleic acid sequencing technologies spurred the development of a new generation of high-throughput lineage tracking methods based on DNA “barcodes” (Blundell and Levy 2014 ; Woodworth et al 2017 ; Kebschull and Zador 2018 ; Masuyama et al 2019 ; Baron and van Oudenaarden 2019 ; Wagner and Klein 2020 ; VanHorn and Morris 2021 ; Dujardin et al 2021 ). In these approaches, individual cells are tagged with unique genetic markers called “barcodes.” Many thousands of cell lineages carrying different barcodes can be tracked within a population over multiple generations using high-throughput sequencing.…”