Developments in biomedical research techniques often develop faster than many scientists can keep up with. Many of the newest technologies — such as CRISPR gene editing and stem cell research — have opened the doors for scientists to explore new fields and find answers to novel questions. These technologies are particularly important for advancing fields of science that require complex models to understand disease.

Cancer is one of the leading causes of death around the world, resulting in nearly 10 million deaths worldwide in 2020, according to the World Health Organization (WHO). The diseases’ complexity and the ability of cancer cells to spread and damage surrounding tissues and organs makes it extremely difficult to treat. The severity of cancer and its prevalence around the world emphasize the need for cutting edge research tools that can mimic the cancerous environment as closely as possible.

For many years, researchers have used cell lines of cancerous cells and model organisms, such as mice and zebrafish, to study the disease and to develop potential therapies. However, the complex nature of cancer and the species differences between model animals and humans make it difficult to directly apply scientists’ findings to the clinics.

To overcome these challenges, scientists are utilizing innovative new methods to understand the complexities of cancer. Indeed, Mo-Fan (Elena) Huang and Megan Fisher, two students at the Graduate School, utilize stem cells in their own research. Writing their review article gave them both the chance to highlight key advancements in this technology that could drive future research and the development of therapies.

What are stem cells, and how are they used?

Stem cells are a unique type of cell that has the ability to change into, or differentiate, into a new type of cell (Mayo Clinic). When this discovery was first made, many scientists used embryonic stem cells in their research, because unlike adult stem cells, these cells could differentiate into any type of cell. However, the ethical limitations of using embryonic stem cells in research slowed the use of this technology in clinical research.

In 2006 Shinya Yamanaka developed induced pluripotent stem cells (iPSCs), which are adult stem cells that have been engineered to behave like embryonic stem cells. Furthermore, iPSCs can be derived from patients with specific cancers, which allows scientists to investigate specific genetic mutations of cancer patients in the lab. This discovery was revolutionary for the cancer biology field and has led to many significant advancements in the field at large.

“It was exciting to see how novel technologies are reshaping our understanding of cancer progression and drug resistance,” Huang said, regarding her recent review article about iPSC technology. “It was very interesting to see how iPSC models are being applied to multiple cancer types to investigate the origins and to better replicate the disease state than conventional models”.

Practical applications of iPSCs in cancer biology

This review article features many advances in the field of cancer biology. Each subfield of cancer biology has its own complications and field of existing knowledge, and iPSCs have assisted in advancing each field in different ways. Huang and Fisher aimed to provide a broad overview of how this technology is used, while also highlighting key findings in various sub-fields of cancer biology.

• Tumors of the nervous system: Tumors of the brain and spinal cord (central nervous system, or CNS) can result in significant impairments in a patient’s mental and physical health. The American Cancer Society predicts that nearly 25,000 malignant tumors will be diagnosed in 2025 alone. Xu, et. al and Huang, et. al utilized iPSC-derived cell lines to understand the mechanisms behind how tumors of the glial cells and neural crest cells, respectively, originate and grow. This research opened the door for new potential therapeutics that can target various steps of the pathways involved in the growth of these tumors. While many scientists utilize iPSCs to understand the mechanisms of tumor growth and formation, others have used these cell lines to identify the exact cell type that begins to become cancerous. Haag, et.al and Anastasaki, et.al identified the originating cells for diffuse intrinsic pontine glioma (a rare form of brain cancer in children) and low-grade gliomas, respectively. Understanding what cell types that cancer can originate from is extremely important for early detection of these diseases.
• Hematological malignancies: While some forms of cancer are isolated to specific organs, others affect widespread systems in the body, such as the bloodstream. Hematological malignancies are a group of blood cancers that involve rapid growth of red blood cells, white blood cells, and platelets. One of the most common forms of hematological malignancies in adults is acute myeloid leukemia (AML). AML consists of uncontrolled growth of myeloblasts, or immature white blood cells that help to fight off infections. To accurately understand how AML functions on a molecular level, Kotini et.al developed iPSC cell lines from 15 patients with various mutations associated with AML. Furthermore, Wang, et.al utilized CRISPR/Cas9 gene editing technology to introduce mutations observed in AML patients into iPSC-derived cell lines. These advancements opened the door for many other groups to investigate and understand the intricacies of AML. Other groups have also utilized similar approaches to create tools to study other hematological malignancies, such as chronic myeloid leukemia, Down syndrome myeloid leukemia, myelodysplastic syndrome, and Fanconi anemia.
• Retinoblastoma: While iPSCs have been used to identify potential mutations that contribute to certain cancers, they have also been used to provide evidence for already existing hypotheses. Cancers of the retina, or retinoblastomas, are most often caused by a mutation in the RB1 tumor suppressor gene. To replicate cells with these mutations in the lab, groups such as Norrie, et. al and Rozanska et. al used iPSCs to create organoid models. Organoid models are 3D cell culture systems that can mimic human physiology extremely accurately. The development of these systems has led to others in the field, such as Li, et. al to provide new evidence that mutations in two alleles of RB1 support tumor formation, which was originally hypothesized by Knudson back in 2001.
• Sarcoma: While some cancers are predominantly caused by mutations in a single gene, other types, such as bone malignancies, have been associated with mutations in multiple different genes. Understanding how mutations in various genes promote cancer is important, as many of these mutations can be inherited by future generations. iPSCs have been used to investigate the mechanisms of mutations in specific genes, such as p53 and RB1. Understanding exactly how these mutations contribute to cancer formation is extremely important not only for treatment development for individuals who have already developed tumors, but also for creating preventatives for individuals who inherit these mutations. The use of iPSCs has also shed light on a different mechanism of sarcoma formation, particularly how the fusion of two genes, HEY1 and NCOA2, promote cancer growth.
• Lung cancer: iPSCs are not only beneficial for understanding how cancers form—they are also great models to determine how effective new treatments are, Marcoux et. al wanted to utilize iPSCs to test the efficacy of pralsetinib, a drug that can target cancers that occur from gene rearrangements. They utilized lung iPSCs that carried a gene rearrangement in RET and found that this drug resulted in lower levels of cancer markers. This study emphasized the importance of iPSC models for the validation of cancer therapeutics.

The future of cancer biology research

The work highlighted in this review article showcases the many advancements in understanding the mechanisms of how cancers form and grow, and in the identification and validation of therapies. iPSCs are an important tool that can be utilized in various sub-fields of cancer biology. Understanding the applications of iPSCs is essential for researchers wanting to answer complex cancer biology questions.

Review articles such as this one highlight key findings in a field that can be easily digested by other researchers who are first being introduced to a method or topic. Reading and writing articles such as this emphasizes the importance of collaboration in science. “Mo-Fan (Elena) was able to help me think more critically about cancer biology and help parse through the insights we wanted to mention in this article,” Fisher said. “This experience highlighted that teamwork and communication are essential in this field.”

“Paper of the Month” is a collaborative effort led by Microbiology & Infectious Diseases PhD candidate Jana Gomez, overseen by Associate Dean for Academic Affairs Francesca Cole, PhD, who collaborate with students to summarize fellow student-authored scientific articles about their biomedical science research and the innovative methods and discoveries they are uncovering.