Blocking One Gene Reversed Pancreatic Cancer's Deadliest Shift

In short: the tumor is not one disease but a shifting coalition, and that reshuffling drives both drug resistance and metastasis.

Why does the gene discovery matter?

The gene MYC showed heightened activity in some of the most aggressive basal cell populations. When researchers blocked MYC in the lab, those cells shifted back toward the less aggressive classical state.

The switch did something else. It made the cancer cells more visible to immune cells, meaning the immune system could in principle recognize and attack them more easily. Much more research is needed before this becomes a therapy, but MYC now stands as a promising drug target.

"Our study provides the most granular view to date of pancreatic ductal adenocarcinoma, revealing how ongoing genetic reshaping drives tumor evolution over the course of disease," said lead investigator Despoina Kalfakakou, PhD, a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center. "These findings suggest that targeting the mechanisms underlying tumor evolution, including MYC, may help restrain the cancer's rapid progression."

Why has immunotherapy failed against this cancer?

The study also offers an explanation for why drugs that unleash the immune system have performed poorly in pancreatic cancer. Certain clones showed increased activity of the TIGIT gene, which produces proteins that help tumors escape immune detection. At the same time, those clones showed reduced activity of PD1 — the very target of many existing immunotherapies.

That combination, high TIGIT and low PD1, may be why PD1-blocking drugs have shown limited effect. Co-senior investigator Aristotelis Tsirigos, PhD, professor of Medicine and Pathology at NYU Grossman School of Medicine, said clinical trials testing inhibitors of MYC and TIGIT are already underway for pancreatic cancer and other malignancies. He called for larger studies examining the different states cancer cells adopt, so treatments can be tailored accordingly.

How was the study done?

The researchers measured gene activity — a technique called transcriptomics — in 443,451 individual cells drawn from 62 tumors in 56 men and women with pancreatic ductal adenocarcinoma. Six patients provided samples both before and after chemotherapy, letting the team track changes linked to treatment.

By tracing each clone's genetic origins and comparing gene-activity patterns, the researchers connected differences in DNA copy numbers — extra or missing copies of genes — with the cell types present in each tumor. That mapping identified which genes, including MYC and TIGIT, were most active at each stage of progression.

"Single-cell clonal analysis offers a better approach to understanding complex cancers, like pancreatic ductal adenocarcinoma, as it develops over time, by mapping how tumors evolve and adapt at each stage of disease progression," said Dr. Tsirigos, who also directs NYU Langone's Applied Bioinformatics Laboratories.

The research was funded by the Sky Foundation and National Institutes of Health grants P30CA016087 and R01CA245005, with additional contributors from Oregon Health and Science University and the University of California San Diego.

For clinicians, the message is direct: pancreatic cancer's lethality lies in its genetic churn, and the first tools built to stall that churn are already in trials.