An analysis of nearly half a million cells from dozens of patients’ tumours reveals how cancer cells continuously reshape their genetic makeup over time, enabling them to evade treatment for one of the deadliest forms of cancer.

Led by researchers at NYU Langone Health and its Perlmutter Cancer Centre, the study focused on pancreatic ductal adenocarcinoma, an often difficult-to-treat disease known to kill nearly 85 percent of people within five years of diagnosis.

While more than half a dozen genes have been implicated in the complex disease, the analysis of single tumour cells provided new insights into how subpopulations of pancreatic cancer cells reconfigure their DNA within tumours over time.

The team’s analysis revealed a diverse set of clones, or clusters of tumour cells that have a similar genetic makeup.

These clones showed striking differences in behaviour, with some evolving to resist therapy and others acquiring the ability to spread rapidly.

The findings suggest that ongoing reshaping of the cancer cells’ DNA fuels both treatment resistance and metastasis.

Past research analysing bulk groups of pancreatic cancer cells had focused on separating them into two subtypes — classical (less aggressive) and basal (more aggressive).

However, the research could not explain how cancer cells shift between these subtypes.

The new findings show that genetic reconfiguration within a tumour enables cancer cells to transition between subtypes.

Publishing in the journal Nature Genetics online, the new study identified specific genetic changes that emerge during tumour evolution, including increased activity of the MYC gene in aggressive tumour cell populations.

Further experiments with pancreatic basal tumour cells showed that blocking MYC activity reverted the cells to the less aggressive classical form and exposed them to more immune cells, potentially making them more vulnerable to immune attack.

“Our study provides the most granular view to date of pancreatic ductal adenocarcinoma, revealing how ongoing genetic reshaping drives tumour evolution over the course of disease,” said study lead investigator Despoina Kalfakakou, PhD, a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Centre.

“These findings suggest that targeting the mechanisms underlying tumour evolution, including MYC, may help restrain the cancer’s rapid progression.”

“Our research also suggests that single-cell clonal analysis offers a better approach to understanding complex cancers, like pancreatic ductal adenocarcinoma, as it develops over time,  by mapping how tumours evolve and adapt at each stage of disease progression,” said study co-senior investigator Aristotelis Tsirigos, PhD, a professor in the Departments of Medicine and Pathology at NYU Grossman School of Medicine and a member of Perlmutter Cancer Centre.

“More broadly, our study results highlight the critical role of clonal diversity, genetic plasticity, and interactions with the tumour’s microenvironment in shaping human pancreatic ductal adenocarcinoma biology,” said Dr. Tsirigos, who also serves as co-director of the Division of Precision Medicine and director of NYU Langone’s Applied Bioinformatics Laboratories.

Among the study’s other key findings was how cell clones influenced the tumour’s ability to evade immune detection, possibly explaining why pancreatic ductal carcinoma resists immune therapy.

The researchers found that in some clones, the TIGIT gene was also more active, producing proteins that help cancer evade immune detection.

In the same clonal cells, activity of the PD1 gene was found to be suppressed, which may help explain why some immunotherapies that target PD1 are rarely effective.

Dr. Tsirigos said that clinical trials using MYC inhibitors or TIGIT inhibitors for pancreatic ductal carcinoma and other cancers are underway, and that his team’s latest findings should encourage larger investigations into different cancer cell states and how to target treatment towards them.

For the study, researchers analysed the genetic activity (using transcriptomics) in clones of 443,451 single cells taken from 62 tumours in 56 men and women with pancreatic ductal adenocarcinoma.

Six patients provided tumour samples pre- and postchemotherapy.

Traditionally, cells have been analysed in bulk for upticks and decreases in gene activity, and not individually, as in the latest analysis.

Single-cell analysis showed that individual tumours contained on average of between two and 11 mixes, or clones, of basal and classical tumour cells.

When the researchers traced the clones’ genetic origins, based on gene activity, they were able to link cell copy variations to the cell composition of tumours.

This was then used to find which genes, such as MYC and TIGIT, were most active at different stages of disease progression.

Besides Drs. Kalfakakou and Tsirigos, NYU Langone researchers involved in this study were Daniel Cameron, MS; Emily Kawaler, PhD; Ziaohong Jing, PhD; Cristina H. Hajdu, MD; Dylan Tamayo, MS; Yoona Shim; Amanda Ackermann, MD, PhD; Daniel Weissinger; Rosmel Hernandez, PhD; Matthew Beier, MD; Dacia Dimartino, PhD; Peter Meyn; Kalina Rice, MS; Shanmugapriya Selvaraj, MS; Cynthia A. Loomis, MD, PhD; Adriana Heguy, PhD; Amanda W. Lund, PhD; and Igor Dolgalev, PhD.

Source: NYU Langone Health / NYU Grossman School of Medicine