Genomic heterogeneity in pancreatic cancer organoids and its stability with culture

Abstract

The establishment of patient-derived pancreatic cancer organoid culture in recent years creates an exciting opportunity for researchers to perform a wide range of in vitro studies on a model that closely recapitulates the tumor. One of the outstanding question in pancreatic cancer biology is the causes and consequences of genomic heterogeneity observed in the disease. However, to use pancreatic cancer organoids as a model to study genomic variations, we need to first understand the degree of genomic heterogeneity and its stability within organoids. Here, we used single-cell whole-genome sequencing to investigate the genomic heterogeneity of two independent pancreatic cancer organoid lines, as well as their genomic stability with extended culture. Clonal populations with similar copy number profiles were observed within the organoids, and the proportion of these clones was shifted with extended culture, suggesting the growth advantage of some clones. However, sub-clonal genomic heterogeneity was also observed within each clonal population, indicating the genomic instability of the pancreatic cancer cells themselves. Furthermore, our transcriptomic analysis also revealed a positive correlation between copy number alterations and gene expression regulation, suggesting the “gene dosage” effect of these copy number alterations that translates to gene expression regulation.

The potential use and experimental validation of genomic instability-related lncRNA in pancreatic carcinoma

“…On the other hand, lncRNAs are associated with the development, progression, treatment, and prognosis of pancreatic cancer. [30,[32][33][34] However, the role of lncRNAs in genomic instability and tumor progression is in its infancy.…”

Differential modulation of cellular phenotype and drug sensitivity by extracellular matrix proteins in primary and metastatic pancreatic cancer cells

“…Both the PDAC and glioblastoma organoids, HCM-CSHL-0092-C25 (ATCC PDM-39) and HCM-BROD-0103-C71 (ATCC PDM-121) respectively, are part of the Human Cancer Models Initiative and were acquired from ATCC. Maintenance of the organoid culture was performed following the instructions from ATCC, as described previously 77 .…”

Pancreatic cancer environment: from patient-derived models to single-cell omics

“…Understanding PDO cellular state heterogeneity is pivotal for elucidating their potential as personalized models. 30 The transcriptomes of each cell within a patient's organoids exhibit remarkable overall similarity, suggesting clonal origins with over 97% occupancy in a single prominent cluster. However, a study revealed two small cell populations, CD133 and AREG, offering valuable insights into the underlying PC pathogenesis.…”