Researchers at NYU Langone Health analyzed nearly half a million single cells from pancreatic cancer tumors, revealing how continuously evolving cell clones reshape their DNA over time. The findings explain how these cell populations evade treatment and spread rapidly across the course of the disease.
Pancreatic ductal adenocarcinoma is known to claim nearly 85 percent of people within five years of diagnosis. For years, scientists studied bulk groups of tumor cells, sorting them into classical and basal subtypes without fully understanding how the cancer shifted between them. Led by researchers at NYU Langone Health and its Perlmutter Cancer Center, the investigation focused on how subpopulations of cells reconfigure their DNA within tumors over time.
Single tumors contain various unique cell clones exhibiting behavioral contrasts, where certain groups develop treatment resistance while others gain fast-spreading traits, according to the study.
Single-Cell Analysis Maps Evolution in 443,451 Cells
Using transcriptomics, the research team examined the genetic activity of 443,451 single-cell clones derived from 62 tumors belonging to 56 female and male patients diagnosed with pancreatic ductal adenocarcinoma. Six patients provided tumor samples pre- and postchemotherapy. By tracking genetic activity within clones inside individual tumors, investigators mapped how tumors evolve and adapt at each stage of disease progression.
This high-resolution approach offered insights into complex cancers by showing how genetic reconfiguration enables cancer cells to transition between classical and basal subtypes. The work was led by Despoina Kalfakakou, PhD, a postdoctoral research fellow at NYU Grossman School of Medicine and Perlmutter Cancer Center. Oregon Health and Science University contributors included co-investigators Motoyuki Tsuda, MD, PhD; Hayley Zimny, and Rosalie Sears, PhD, while University of California San Diego personnel featured Lidong Wang, PhD; Qi Su, PhD; Sungsik Kim, PhD; Hannah Carter, PhD; Theodore Welling, MD; along with co-senior study investigator Diane Simeone, MD. Additional study authors included 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; and Cynthia A. Loomis, MD, PhD.
The analysis showed that distinct clones behave in fundamentally different ways. Some populations evolve therapeutic resistance, while others acquire rapid spreading capabilities. The constant internal reshaping fuels both metastasis and drug evasion.
MYC and TIGIT Genes Drive Immune Evasion
Disrupting processes driving tumor development, such as MYC, could potentially slow the malignancy’s aggressive advancement. Specific cell clones shaped the tumor’s capacity to bypass immune surveillance, offering a potential rationale for why pancreatic ductal carcinoma is unresponsive to immunotherapy. Investigators discovered TIGIT gene expression within select clones, leading to the creation of proteins that assist the cancer in avoiding immune detection. In those identical clonal cells, PD1 gene expression appeared reduced, which could clarify why certain therapies directing themselves at PD1 show limited success.
Researchers Test Inhibitors to Intercept Deadly Cancers
The findings arrive as researchers pursue new methods for early intervention, seeking to subdue one of the world’s deadliest cancers through a strategy known as cancer interception.
Ongoing tests evaluating MYC or TIGIT inhibitors against pancreatic ductal carcinoma and alternative malignancies currently progress, and these recent discoveries ought to inspire studies exploring varied cancer cell conditions alongside customized therapeutic strategies. Reporting by Heidi Ledford for Nature from Seattle, Washington highlights that prospects for new treatments are at an all-time high as researchers look for ways to boost survival by treating the disease early.