Cancer: Rare ‘Super-Cells’ Drive Tumor Growth & Treatment Resistance

A new study suggests that cancer’s progression isn’t driven equally by all tumor cells, but by a small, adaptable group capable of surviving treatments. These cells appear to play a central role in transforming initial lesions into aggressive tumors.

The Rise of ‘Super-Stem’ Cells in Cancer

Researchers at Memorial Sloan Kettering Cancer Center have discovered that a small number of cancer cells, possessing an exceptional ability to change their identity and behavior, appear to be the primary engine driving cancer progression and the development of treatment resistance. Published in the journal Nature, the study details how these “highly plastic” cells can rapidly generate multiple types of tumor cells and help cancer survive therapies.

To investigate, the research team developed a sophisticated system for marking and tracking these cells in a mouse model of lung adenocarcinoma, both before and after various treatments. Their findings indicate that while initially rare, these cells become increasingly numerous as the tumor advances.

Did You Know? The proportion of these highly plastic cells increases as the disease progresses, from approximately 3% in precancerous lesions to around 15% in primary tumors and up to 30% in metastases.

Mimicking Tissue Repair

The researchers compare these highly plastic cells to “super-stem” cells. In healthy tissues, stem cells replace lost or damaged cells, with each organ having its own specialized stem cells. However, when injury occurs, repair programs activate, giving cells greater flexibility to generate a wide range of cell types.

This study reveals that cancer cells can exploit these normal tissue repair mechanisms to their advantage. As we age, cells accumulate mutations, most harmless, but the difference between a premalignant lesion and aggressive cancer lies in a cell’s ability to enter this highly flexible, regenerative state.

These cells aren’t essential for initiating a tumor, but are critical for its development, progression, rapid growth, treatment resistance, and potentially, its spread. Experiments on mice showed that early removal of these cells largely prevented mutated cells from evolving into cancer, and removing them from established tumors significantly reduced tumor size.

Expert Insight: This research shifts the understanding of cancer progression away from a fixed hierarchy of stem cells maintaining the tumor, and towards a more dynamic model where cells can transition into a plastic state in response to local signals, mirroring the body’s own healing processes.

Potential for New Therapies

When tumors are treated with chemotherapy or targeted therapies, such as KRAS inhibitors, these plastic cells can quickly adapt and give rise to drug-tolerant cell types, allowing the tumor to recover. However, the study also identified a potential vulnerability: a protein on the cell surface called uPAR.

In experimental models, researchers successfully eliminated these highly plastic cells using CAR T-cells targeted against uPAR, achieving a strong anti-tumor response. This strategy could be effective because uPAR is primarily expressed by cells activating tissue-healing mechanisms, not most healthy cells.

The study suggests this mechanism may not be limited to lung cancer, potentially applying to other carcinomas – tumors arising from cells lining organs and tissues, representing 80–90% of all cancers. Researchers are continuing to explore strategies to target these cells, including small molecule drugs, antibody-drug conjugates, and CAR T-cell therapies, as well as disrupting the molecular pathways supporting this cellular state. Further studies are underway to determine if these findings hold true for other types of carcinoma.

Frequently Asked Questions

What role do these ‘plastic’ cancer cells play?

These cells are critical for the development and progression of cancer, the emergence of rapid growth, the development of resistance to treatment, and potentially, the spread of cancer.

How were these cells studied?

Researchers developed a system to mark and track these cells in a mouse model of lung adenocarcinoma, both before and after different treatments.

Is there a potential target for treating these cells?

The protein uPAR, found on the surface of these cells, has been identified as a potential target, and researchers have had success eliminating these cells using CAR T-cells directed against uPAR in experimental models.

What implications might this research have for future cancer treatments?