Helping Cancer Cells “Grow” Could Be the Key to a Cure

by Harrison Ngue

Cancer is one of the world’s deadliest diseases, causing nearly 10 million deaths worldwide annually. It begins when cells in the body grow and divide uncontrollably, forming tumors that invade tissues and disrupt normal body functions. While traditional cancer treatments like chemotherapy and radiation focus on killing these rapidly dividing cells, researchers at MIT’s Koch Institute for Integrative Cancer Research are exploring a different approach: pushing cancer cells to “grow up” into healthy, functional cells. In a recent study, they discovered that “stressing” cancer cells can encourage them to mature.

This strategy is particularly promising for acute myeloid leukemia (AML), a blood cancer that is difficult to treat. The American Cancer Society estimated that in 2024, about 20,800 people in the United States would be diagnosed with AML, with a staggering 68.1% dying within five years of diagnosis. What makes AML unique is that it does not just involve the uncontrolled division of cells—it also involves a failure of blood cells to differentiate, or “grow up,” into mature, healthy blood cells (Figure 1). This has two consequences: first, the body is unable to produce enough mature blood cells to carry oxygen and fight infections, and second, the buildup of immature cells physically crowds out healthy cells. This leaves patients suffering from severe fatigue, frequent infections, and excessive bleeding.

**Figure 1.** Acute myeloid leukemia (AML) is a type of cancer where immature blood cells multiply rapidly without maturing into functional cells, leading to harmful buildup in the body.

Due to the unique nature of AML, its treatment strategies often include approaches beyond traditional cancer therapies. While chemotherapy is still commonly used, AML therapies also focus on encouraging these immature cells to differentiate. This restores healthy levels of mature blood cells, improving blood function overall. Differentiation therapy has already improved treatments for certain forms of AML—for example, treatment with a compound known as all-trans retinoic acid promotes maturation of blood cells by activating genes encoded by DNA, or instructions for a cell, to differentiate. Combined with arsenic trioxide, these treatments have dramatically improved patient outcomes.

A newer promising differentiation strategy targets an enzyme called dihydroorotate dehydrogenase, which is essential for producing nucleotides. Nucleotides are the building blocks of DNA needed for cell replication and growth. If you recall that cancer begins when cells replicate uncontrollably, it makes sense that blocking what cells need to replicate and grow would be imperative for stopping the spread of cancer. Blocking this enzyme lowers nucleotide levels, which has shown potential to induce differentiation. However, why nucleotide depletion also triggers maturation remains unclear. Understanding this mechanism could lead to more precise AML treatments and new options for other cancers where cells fail to mature.

Replication Stress is a Key to Differentiation

Recently, researchers found that when they blocked immature blood cells from making nucleotides, something interesting happened: the cells encountered replication stress. As the cells tried to replicate their DNA, the shortage of nucleotide building blocks created a sort of “pressure” within the cell, making it difficult for the cells to maintain their cancerous properties. This stress prompted them to start maturing (Figure 2).

**Figure 2.** **(a)** Normally, AML cancer cells have high levels of available nucleotides, allowing them to grow, divide, and form tumors. **(b)** When nucleotide levels are low, AML cells experience stress during DNA replication, pushing AML cells to mature into functional blood cells and lose their cancerous traits.

To confirm that replication stress—and not just a lack of nucleotides—was driving this process, the researchers explored the difference between these two conditions. Low nucleotide levels mean there aren’t enough building blocks for cells to copy their DNA, which can cause replication stress—a state where the process of copying DNA becomes difficult and error-prone. However, replication stress doesn’t always require low nucleotide levels. It can also occur for other reasons, like obstacles in the DNA or machinery problems during copying. By inducing replication stress without depleting nucleotides, the researchers showed that it was the stress on DNA replication itself—and not just the lack of building blocks—that caused the cells to mature.

How does replication stress promote cell differentiation?

Though it was clear that replication stress promotes differentiation, the scientists wanted to understand what biological processes connect these two events. They found that replication stress triggers changes in how a cell’s DNA is organized, making certain parts more accessible. This process, known as chromatin remodeling, controls which genes are on or off (Figure 3), effectively reorganizing the cell’s “blueprint” to activate genes involved in maturation.

While it was clear that replication stress helps cells mature, the scientists wanted to figure out how exactly this happens. They discovered that replication stress changes how the DNA in a cell is packaged. Normally, DNA is tightly packed, like a book with its pages glued shut, to save space and protect the instructions inside from being read all at once. But replication stress makes specific sections of the DNA more open, like loosening the “glue” so the pages can be read. This process, called chromatin remodeling, allows certain genes to be more easily read and used by the cell. These active genes provide the blueprint for the cell to mature, while other genes remain inactive. In this way, nucleotide shortages trigger changes in DNA organization, which then activate the genes needed for the cell to mature and stop acting like a cancer cell (Figure 3).

**Figure 3**. How replication stress pushes cells to mature. **(a)** Replication stress changes how DNA is wrapped, leading to more activation of genes that encourage cell maturation.

The timing of replication stress also matters. The researchers discovered that applying replication stress at random points in a cell’s life cycle does not always lead to differentiation. Instead, replication stress is most effective when cells are actively copying their DNA in preparation for cell division. Cancer cells, which divide more frequently than normal cells, spend a lot of time in this phase, making them particularly sensitive to stress. This sensitivity presents a valuable opportunity for treatment, as it provides a broad window during which therapies can encourage these cells to mature.

What Do These Findings Mean for Cancer Treatment?

This study could have a big impact on how we approach AML treatment. By promoting differentiation rather than killing cancer cells outright, this strategy could help reduce tumor growth in a gentler, more targeted way. Since many cancers involve immature, fast-dividing cells, this strategy could be applied beyond AML to other cancers where differentiation is blocked.

Guiding cells to mature could complement traditional treatments. By encouraging differentiation, this approach could reduce the need for aggressive chemotherapy, which often causes side effects like fatigue and tissue damage. This makes it particularly beneficial for older patients or those with weakened immune systems. As research advances, scientists hope to refine differentiation therapies to integrate seamlessly with conventional approaches, offering patients a promising new path.

Harrison Ngue is an MD-PhD student at Harvard Medical School and the Massachusetts Institute of Technology. He graduated from Harvard College with a degree in biomedical engineering and history of science. His research focuses on cancer biology. He is the founder of the animated educational YouTube channel “Powerhouse of the Cell.” Twitter/X: @harrison_ngue

Cover image by doodlartdotcom on pixabay. Figures made using biorender.com.

For more information:

The American Cancer Society has a brief primer about acute myeloid leukemia and its current treatments.
This YouTube video by the Amoeba Sisters illustrates the process by which cells mature and become specialized.
Check out this article from the University of Chicago to learn more about how encouraging cancer cells to mature can be a viable treatment strategy.
In this interview, Dr. David Sykes, a physician-scientist at Massachusetts General Hospital who specializes in blood cancers, discusses recent advances in differentiation therapy.
To learn about various ways DNA can be organized, making certain genes more accessible than others, read this article from Nature Education.