A small number of cancer cells with the ability to change their identities and behaviours 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 tumours from forming, according to a new study by researchers at Memorial Sloan Kettering Cancer Centre (MSK).

Their findings were published 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 tumour.”

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 specialising 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 programmes 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 programmes 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 tumour.

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 tumour, you can basically prevent mutated cells from ever becoming cancers,” Dr. Tammela adds.

The team also found that eliminating plastic cells from established tumours 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 tumours grow, the researchers found. They account for about 3% of cells in precancerous lesions, about 15% in established tumours, and up to 30% in metastases, Dr. Tammela says.

When a tumour 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 tumour 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 recognise 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 programme but not in most normal, healthy cells,” he adds, “and eliminating them cuts off a tumour’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 tumour.

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 tumour formation and later in additional cells as the tumour progresses.

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

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

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.

Article: Critical role for a high-plasticity cell state in lung cancer

Source: Memorial Sloan Kettering Cancer Center