Understanding cancer thanks to the boundless potential of stem cells

What do you want to be when you grow up? It’s a common question posed to children and adolescents learning about the endless possibilities of adult life. Many factors play into our life’s trajectory, from personal interests to meeting basic needs to environmental influences — we grow and adapt to meet everyday challenges and forge a path for ourselves.

On the cellular level, we undergo a similar process.

Much like how we, as people, try to differentiate ourselves and seek purpose in life, stem cells also undergo certain processes to specialize and support tissue functions. This ability to specialize into a wide array of cell types is unique to stem cells and is a source of immense interest to researchers. At St. Jude, scientists seek to understand the mechanisms driving stem cell identity, with boundless potential for treating disease.

Self-renewal: the endless possibility of stem cells

The term stem cell gets used often — in news articles, biology textbooks and even TV medical dramas. But what are stem cells?

Stem cells are the clay that becomes the bricks that make a house — the raw material. During cell division, the resulting two daughter cells may become two stem cells, a stem cell and a more differentiated cell type or two differentiated cell types. This feature of self-renewal and differentiation is unique to stem cells. Other cells, such as muscle cells, blood cells or nerve cells, have a limited capacity for replication, only able to do so for a short period, if at all.

“What differentiates stem cells from other cell types is the ability to self-renew long-term for the organism’s entire life,” said Dirk Loeffler, PhD, St. Jude Department of Hematology. “Many cell types can self-renew, but their self-renewal ability is limited to days, weeks or months, maybe. But stem cells are unique because they can do it for extended periods.”

This self-renewal process is critical to the organism because it maintains a reserve of malleable cell material that can become what the body needs, depending on the circumstances. However, the factors regulating stem cell self-renewal and differentiation remain poorly understood. Understanding how a stem cell knows what cell type to become is a mystery that researchers like Loeffler aim to uncover.

Studying stem cell differentiation presents challenges

Many factors are involved in stem cell regulation, depending on where the cell is in its life cycle and what signals it receives from its surroundings. Some signals are received from the microenvironment, such as nearby cells that communicate either by direct contact or by secreting signaling molecules. Other factors regulate stem cell behavior independently from other cells or signals from the surrounding bone marrow microenvironment.

“Under normal circumstances, most blood stem cells are in a quiescent state, meaning they are dormant and they’re not dividing. It is only when the stem cells are needed, for instance, during infections, that they become active. Depending on the signals the cell receives, the cells either self-renew, differentiate or die, according to the body’s needs,” explained Loeffler.

Given the complex nature of its processes, observing stem cell behavior presents a distinctive challenge to researchers: How does one capture cell fate decisions when we do not know when exactly they occur?

Stem cell proliferation and differentiation do not happen in a single moment; they unfold over many different time scales. Another factor that poses a challenge for scientists is stem cells’ heterogeneous nature. Research over the last decade has demonstrated that stem cells can possess different properties. These properties might bias them toward differentiating into one lineage over another, which leads to variances in the number of produced mature blood cells and the timing of cell fate decisions.

“We have heterogeneity between cells even in the most highly purified population of blood stem cells. This means not all stem cells respond to signals the same way, and we find stem cells that make different decisions and execute these decisions at different times. So, we have a lot of confounding factors that blur our view on the mechanisms involved in stem cell fate regulation,” Loeffler said.

Multidisciplinary research unravels the mysteries

For Loeffler and his lab, timing is a crucial element in their research. Some processes happen rapidly — milliseconds — others develop over many weeks. To address this concern, his group develops novel and advanced microscopy tools for long-term time-lapse imaging, taking nonstop images of hematopoietic stem cell (HSC), or blood-related stem cell, samples over the course of weeks. This process generates a massive amount of data and allows his team to observe stem cells’ progression and interactions, track cell lineages and determine when key events — cell division, cell death and differentiation — occur across many cell generations.

“By having these lineage trees, we can now identify when the cells make decisions. We can then start to understand what molecular processes are at play at the decision-making point. This is something that is usually missed in a standard snap-shot type of analysis,” Loeffler said.

To make sense of their results, Loeffler and his lab take a multidisciplinary approach. Because time-lapse imaging generates more data than any human could hope to process efficiently, having access to computational tools and people with complementary expertise allows the team to analyze vast amounts of data efficiently to filter and refine their data to pinpoint the precise timing of stem cell fate decisions.

Engineering also plays a crucial role in advancing the understanding of stem cell fate regulation. While there are companies that produce off-the-shelf components for research, such as tools for advanced microscopy, commissioning one to build a custom prototype for a single experiment is typically not feasible: the cost is exorbitant and often requires purchasing multiple units. Integrating engineering expertise into the lab provides the freedom and flexibility to think creatively and build custom research equipment that enables novel ways for how the researchers can approach certain questions. 

“If you combine two or three sets of expertise, suddenly, you create synergisms and new ideas that you would likely not have or couldn’t pursue within a single field. This interdisciplinary approach is required to address today’s biomedical questions and to move science forward. I’m convinced that the research questions we’re trying to answer today need this interdisciplinary work to move us forward,” Loeffler enthused.

A cell’s fate can influence disease outcomes

Cancer is a disease of cells — cells growing too fast and too much, spreading too far. Stem cells, with their ability to grow and develop into any kind of cell, provide a unique lens to think about the unchecked growth so characteristic of cancer. Recognizing the mechanisms governing cell fate decision could have far-reaching applications for cancer research in terms of understanding how stem cell mutations propagate and how clinicians can use these mechanisms to treat their patients.

One question that Loeffler and his lab aim to answer is how a mutation in an HSC can affect stem cell self-renewal. When a mutated HSC self-renews more frequently than its normal counterpart, mutant HSCs and their offspring with the same genetic mutation expand and outnumber normal blood cells over time — a process called clonal hematopoiesis, which occurs in the very early stages of diseases, such as leukemia.

Research has found that such HSCs gain a fitness advantage because of their mutation, which changes cell fate decisions, allowing them to be more resilient and to create more mutant hematopoietic cells. Beyond understanding the effects of clonal hematopoiesis, Loeffler’s lab seeks to uncover the circumstances that lead to HSCs acquiring additional mutations and becoming cancer cells, with the hope that, if those mechanisms can be understood, scientists could develop interventions to mitigate or prevent those circumstances entirely.

“When you know how cells make decisions, you can manipulate these decisions,” Loeffler explained. “If you can manipulate these decisions, that means you can produce the cell type you’re interested in or, in the context of cancer, remove mutant stem cells to prevent disease progression and cancer.”

Children and adolescents can have boundless potential to grow, learn, contribute and ultimately become an adult driven by purpose. Stem cells are the embodiment of boundless potential, not just in what they may or may not become but in the impact those cell fate decisions can have on health and disease. They are a starting point upon which researchers can gain new insight into how conditions such as cancer occur — and how they can be stopped.