MSK Team Develops Method to Track Cells with High Plasticity

Memorial Sloan Kettering Cancer Center researchers have developed a sophisticated method to highlight and track highly plastic cancer cells that drive tumor growth and treatment resistance. These adaptable cells, present in small numbers, enable cancer progression by mimicking injury-repair programs normally reserved for stem cells.

The team, led by Tuomas Tammela, applied this method in mouse lung adenocarcinoma models to track plasticity across tumor development. "Scientists have suspected that it's really a small subset of cells that drives cancer's ability to adapt and resist treatment, but efforts to study and target these cells directly have been limited," says Tammela. "Our goal was to pinpoint these cells and understand their activity over the life of a tumor." 

Jason Chan, co-first author of the study pubished in Nature, describes these cells as "super stem cells" that activate flexible regenerative states during tissue injury. "The problem is when cancer cells borrow these programs that are normally only available to stem cells," Chan explains. Unlike stable cancer stem cells, these represent a dynamic state acquired through injury-like signals, transitioning tumors from hyperplasia to adenocarcinoma.

Chun-Hao Pan, the other first author, notes that most aging-related mutations never become cancerous without this plasticity. These cells become essential for generating fast-growing progeny, acquiring drug resistance, and potentially metastasizing. Their numbers increase with tumor advancement: roughly 3% in precancerous lesions, 15% in established tumors, and up to 30% in metastases.

Current treatments like chemotherapy or KRAS inhibitors fail to eliminate these cells, allowing tumor regrowth. Early elimination prevents cancer formation entirely, while targeting them in advanced tumors causes significant shrinkage by blocking resistance pathways. "In our experiments, if we kill off these plastic cells very early in the initiation of a tumor, you can basically prevent mutated cells from ever becoming cancers," Tammela states.

The study identifies uPAR, a surface protein unique to these cells, as a promising target. Collaborating with Zeda Zhang and Scott Lowe, the team used uPAR-recognizing CAR T cells to produce strong antitumor responses. "We believe the approach could be effective because uPAR is present in cells with this repair-like program but not in most normal, healthy cells," Tammela adds.

While studied in lung cancer, the findings likely apply to epithelial carcinomas, which represent 80-90% of all cancers.