One of cancer’s greatest survival strategies is cellular plasticity – the ability to change cellular identity and adopt new behaviors that allow cancer cells to invade surrounding tissues or evade treatment. Pancreatic ductal adenocarcinoma (PDAC), which has an extremely poor prognosis, offers a striking example of this cellular plasticity. Tumors can shift between two distinct cellular identities, known as the classical and basal subtypes, each with unique biological characteristics and different responses to treatment.
Researchers from the Kugel Lab in the Human Biology Division, in collaboration with the Blanco-Melo and Cheung labs at Fred Hutch and researchers at the University of Toronto, have identified a protein called ZNF274 as an important epigenetic switch that helps determine which cellular identity pancreatic cancer cells adopt. The team first became interested in ZNF274 while searching for proteins that regulate cellular plasticity in PDAC. Previous studies had shown that ZNF274 helps organize DNA into tightly packed, inactive regions of the genome, but its role in pancreatic cancer remained unknown.
“ZNF274 caught our attention because we suspected it might regulate previously unknown pathways in cancer,” explained Dr. Jessica Gianopulos, a former postdoctoral researcher in the Kugel lab. “We hypothesized that loss of ZNF274 modulates cell differentiation programs and impacts cellular plasticity in PDAC,” added Dr. Sita Kugel.
That hypothesis proved correct. When the researchers removed ZNF274 from pancreatic cancer cells, the cells underwent a dramatic shift in identity. Cells with a classical identity adopted characteristics associated with the basal subtype, including changes in their shape and the activation of genes associated with metastasis.
The identity shift also revealed a therapeutic opportunity. Basal-like cells are more sensitive to drugs that block CDK7, a protein that helps drive cancer cell growth and survival. By deliberately shifting cells into this more treatment-responsive state, the researchers dramatically increased the effectiveness of CDK7 inhibitors in lab models. They also found that pairing a CDK7 inhibitor with an epigenetic drug that promotes this identity shift made the treatment even more effective.
“This work opens an entirely new avenue of epigenetic regulation that controls cancer cell plasticity,” Gianopulos explained. “ZNF274 is one of those connection points. Continued exploration of this epigenetic landscape could better refine our understanding of what makes a cancer cell sensitive or resistant to a therapy.”
Together, these findings suggest that an emerging therapeutic strategy known as state-gating could offer a new way to treat pancreatic cancer. Rather than viewing cellular plasticity as an obstacle to treatment, the idea is to first drive cells into a more treatment-responsive state before targeting the cancer. That idea is already beginning to move beyond the bench, with the Kugel lab preparing to launch a clinical trial testing CDK7 inhibition in basal pancreatic cancer.
For patients with pancreatic cancer, changing a tumor's identity may be a clever way of destroying the tumor.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Sita Kugel, Kevin Cheung, and Daniel Blanco-Melo contributed to this research. This research was supported by the Cellular Imaging, Experimental Histopathology, and Preclinical Modeling Shared Resources of the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium.
The spotlighted research was funded by the National Institutes of Health, the V Foundation for Cancer Research, The Fred Hutchinson Cancer Center Human Biology Pilot Grant, the ARCS Foundation Fellowship, and the Searle Scholars Program.
Gianopulos JE, Schutter A, Dobersch S, Wallace-Povirk A, Kogut SE, Doak A, Chanana P, Ge S, Mangino L, Yamamoto N, Boila LD, Padilla-Galvez M, Hui J, Rhoads N, Gifford RJ, Cheung KJ, Blanco-Melo D, Notta F, Kugel S. 2026. ZNF274 constrains lineage plasticity and drives intrinsic resistance to CDK7 inhibitors in pancreatic cancer. Nature Communications. DOI: 10.1038/s41467-026-73380-x
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.