Small number of ‘highly plastic’ cancer cells drive disease progression and treatment resistance

A small number of cancer cells with the ability to change their identities and behaviors appear to be a key driver of cancer progression and its ability to evolve resistance to treatment.

Targeting this subpopulation of “highly plastic” cells may make current treatments more effective and could potentially help prevent aggressive tumors from forming, according to a new study by researchers at Memorial Sloan Kettering Cancer Center (MSK). Their findings were published January 21 in Nature.

“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 study senior author Tuomas Tammela, MD, PhD, an investigator at MSK’s Sloan Kettering Institute. “Our goal was to pinpoint these cells and understand their activity over the life of a tumor.”

For this study, the team used a mouse model of lung cancer and developed a sophisticated method that allowed them to highlight and track cells with high plasticity before and after different treatments.

And while the study was conducted specifically in lung adenocarcinoma models, the findings may hold true for other types of epithelial cancer — carcinomas that arise in the cells that line our organs and tissues — which account for 80-90% of all cancers, the researchers note.

‘Like Super Stem Cells’

You might think of these highly plastic cells as being like super stem cells, says study co-first author Jason Chan, MD, PhD, a medical oncologist specializing in sarcoma and a postdoctoral researcher in the Tammela Lab.

In healthy tissues, stem cells make new cells to replace those that are lost or damaged through normal wear and tear, he explains. Most organs maintain themselves with resident stem cells tailored to that type of tissue — alveoli or bronchial cells in the lung, skin cells, intestinal cells, and so on.

But when an injury occurs, special injury repair programs get triggered that put stem cells in an even more flexible state — “like a super stem cell.” This allows the cell to expand its capabilities and produce a much wider variety of new cells.

“The problem is when cancer cells borrow these programs that are normally only available to stem cells,” Dr. Chan says.

Injury-Healing Programs Highjacked by Cancer

Indeed, it’s these highly flexible — highly plastic — cell states related to injury repair that cancer hijacks, says the study’s other first author, Chun-Hao Pan, PhD, a postdoctoral researcher in Dr. Tammela’s lab.

“As we age, our cells accumulate small mutations that have the potential to become cancer — though the vast, vast majority of them never do,” he says. “And what we uncovered is that what separates a premalignant lesion from one that becomes an aggressive cancer is the cells’ ability to enter into this highly plastic, injury‑regeneration-like state.”

These highly plastic cells aren’t necessary to initiate a tumor. But they’re critical to cancer’s progression, the team found — including its ability to give rise to fast-growing cells, to evolve resistance to treatment, and to potentially help the cancer spread to other parts of the body.

“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,” Dr. Tammela adds.

The team also found that eliminating plastic cells from established tumors caused them to shrink significantly.

“It stalls their progression,” Dr. Tammela says, “because it blocks the tricks cancer cells use to develop resistance to treatment.”

Targeting Highly Plastic Cells

Highly plastic cells become more abundant as these tumors grow, the researchers found. They account for about 3% of cells in precancerous lesions, about 15% in established tumors, and up to 30% in metastases, Dr. Tammela says.

When a tumor is attacked with chemotherapy or a targeted therapy like a KRAS inhibitor, these highly plastic cells can rapidly adapt into drug‑tolerant cell types — preserving a core part of the tumor to flourish anew, even as many of the other cancer cells are killed off by the treatment.

“So targeting this population of cells could present an opportunity for making current therapies more effective by eliminating pockets of resistant residual disease,” Dr. Tammela says. “It could also potentially help prevent aggressive cancer from forming in populations that are at high risk — such as smokers in the case of lung cancer.”

A Vulnerability in Highly Plastic Cells: uPAR

The study makes a strong case that these highly plastic cancer cells are actionable targets by zeroing in on a protein called uPAR, which is found on the surface of the cells.

In their mouse models, the researchers collaborated with MSK colleagues Zeda Zhang, PhD, and Scott Lowe, PhD, to successfully kill the plastic cells with CAR T cells that recognize uPAR on their surface. This produced a robust antitumor response and highlights an immediate therapeutic potential.

“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,” he adds, “and eliminating them cuts off a tumor’s ability to adapt and regenerate.”

The Difference Between Highly Plastic Cells and Cancer Stem Cells

In classic models of cancer, cancer stem cells are a rare, stable subpopulation that acts like normal stem cells — both renewing itself and continuously generating the other cancer cell types that sustain a tumor.

The MSK study identifies a different phenomenon: a high-plasticity cell state that cancer cells acquire in response to local injury-like signals — initially in a small subset early in tumor formation and later in additional cells as the tumor progresses.

Rather than being akin to steady-state stem cells, these highly plastic cells more closely resemble the temporary, regenerative program that normal tissues activate in response to an injury, Dr. Tammela explains.

In this model, highly plastic cells help a tumor transition between states: from hyperplasia (abnormal cell overgrowth) to adenoma (benign tumor) and, ultimately, to adenocarcinoma (malignant tumor).

Next Steps for the Research

The research team is exploring ways to target these highly plastic cells with variety of approaches, including small-molecule drugs, antibody drug conjugates, and CAR T cells — as well as investigating opportunities to disrupt the molecular pathways that support and sustain the plastic cell state itself.

They’re also conducting additional research to test the applicability of their findings to carcinomas beyond lung cancer.

Meanwhile, Dr. Chan is preparing to launch an independent lab at Cedars-Sinai in Los Angeles, where he plans to explore highly plastic cells’ implications for sarcoma, a type of soft tissue cancer that is notoriously resistant to chemotherapy.

Additional Authors, Funding, and Disclosures

Additional authors of the paper include Jonathan Rub, Klavdija Krause, Emma Brown, Gary Guzman, Hannah Styers, Griffin Hartmann, Zhuxuan Li, Xueqian Zhuang, Doron Betel, and Yan Yan.

The work was supported by the National Institutes of Health (K08-CA267072, R01-AG054720, R01-CA270116, R01-CA293718); the Linn Fund for Sarcoma Research; an American Cancer Society award (PF-25-1422234-01-PFCBI); a Boehringer Ingelheim Fond doctoral fellowship; a Damon Runyon postdoctoral fellowship (2467-22); a postdoctoral fellowship from the American Federation for Aging Research; the St. Louis Ovarian Cancer Awareness Research Grant for Ovarian Cancer from the Foundation for Women’s Cancer; a New York Stem Cell Science NYSTEM training award (C32559GG); the Center for Stem Cell Biology at MSK; the Druckenmiller Center for Lung Cancer Research at MSK; the National Institute of Aging (R01-AG065396); the MSK Technology Development Fund; the Mark Foundation for Cancer Research; the Howard Hughes Medical Institute; the Geoffrey Beene Cancer Research Center at MSK; the Sigrid Jusélius Foundation; the National Natural Science Foundation (82373443); and Fundamental Research Funds for Central University (2662025SYPY005); the Huazhong Agricultural University Pilot Project Fund; an AACR Next Generation Transformative Award; Josie Robertson and Rita Allen Scholarships; and the National Cancer Institute National Cancer Center Support Grant to MSK (P30-CA08748).

The research relied on core facilities at MSK including Antitumor Assessment, the Integrated Genomics Operation, Flow Cytometry, Molecular Cytology, and the Single Cell Analytics and Innovation Lab.

Dr. Tammela is a scientific advisor with equity interests in Lime Therapeutics. His spouse is an employee of and has equity in Recursion Pharmaceuticals. The Tammela Laboratory receives funding from Ono Pharma related to targeting the high-plasticity cell state, although this funding did not directly support this work. Dr. Lowe is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus, PMV Pharmaceuticals, Faeth Therapeutics, and Senecea Therapeutics, and is a consultant for Fate Therapeutics. He has equity in a joint venture developed by MSK and a cell therapy company to develop senolytic cell-based therapies for noncancer indications. The company has licensed MSK intellectual property, including huPAR binders. The Mark Foundation provided the Endeavor Award to Scott Lowe for “Harnessing Senescence Biology for Immune Oncology.”

Read the article: “Critical role for a high-plasticity cell state in lung cancer,” Nature. DOI: 10.1038/s41586-025-09985-x