A Novel Approach to Cancer Treatment Identified by Yale Scientists

Researchers from Yale University have unveiled a groundbreaking study that highlights the critical role additional chromosomes play in cancer cell proliferation. The removal of these extra chromosomes stymies the formation of tumors, opening up a new targeted strategy for cancer therapy.

A recent investigation from Yale’s team establishes that extra chromosomes are not merely incidental in cancer cells but are, in fact, vital for tumor growth. Eliminating these supplementary chromosomes puts a halt to tumor development. According to the study’s authors, this discovery suggests that a targeted approach against these extra chromosomes could offer a new pathway for cancer treatment.

This research was recently documented in the scientific journal, Science.

In a typical human cell, there are 23 pairs of chromosomes. Any extra chromosomes present are a condition referred to as aneuploidy.

Jason Sheltzer, Assistant Professor of Surgery at Yale School of Medicine and the senior author of the paper, noted, “In normal tissue like skin or lungs, nearly all cells have the correct number of chromosomes. However, aneuploidy has been observed in almost all types of cancer for more than a century.”

The role these extra chromosomes play in cancer had previously been ambiguous. It was not known whether they were a cause or a consequence of cancer.

Sheltzer, also a researcher at Yale Cancer Center, stated, “For many years, aneuploidy was something we could observe but not alter. The tools were simply not there. But in this research, we utilized CRISPR gene-editing technology to forge a new method to eradicate entire chromosomes from cancer cells. This technological advancement will help deepen our understanding of how these chromosomes operate.”

This study was jointly led by Vishruth Girish, currently an M.D.-Ph.D. student at Johns Hopkins School of Medicine, and Asad Lakhani, now a postdoctoral researcher at Cold Spring Harbor Laboratory.

The research team employed a novel technique they coined as Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT). They applied this method to melanoma, gastric cancer, and ovarian cell lines, particularly targeting and eliminating an abnormal third copy of the long segment, known as the “q arm,” of chromosome 1. This abnormality is linked to several types of cancers and is indicative of disease progression.

Sheltzer remarked, “When we purged the genomes of these cancer cells of aneuploidy, their malignancy was compromised and they were unable to form tumors.”

The team posited that cancer cells might be “addicted” to aneuploidy, a concept reminiscent of earlier findings around “oncogene addiction.”

In exploring how an additional copy of chromosome 1q could foster cancer, the team observed that multiple genes, when overrepresented due to the extra chromosome, stimulated cancer cell growth. This overexpression also revealed potential vulnerabilities in cancer cells that could be exploited therapeutically.

Prior studies had established that a gene on chromosome 1, known as UCK2, activates certain medications. In this study, cells with an additional chromosome 1 were more susceptible to these medications due to UCK2 overexpression. This increased sensitivity could potentially guide cellular evolution away from aneuploidy, reducing the potential for malignancy.

Sheltzer concluded, “This informs us that aneuploidy itself could serve as a therapeutic target for cancer treatment. Since nearly all cancers are aneuploid, targeting those specific cells could be a way to treat cancer while minimizing damage to normal tissue.”

While these discoveries are promising, further investigation is essential before advancing to clinical trials. The team is eager to extend their work into animal models, evaluate additional medications and other forms of aneuploidy, and collaborate with pharmaceutical companies to move toward clinical testing.

For the research paper’s reference: “Oncogene-like addiction to aneuploidy in human cancers” by Vishruth Girish, Asad A. Lakhani, et al., published on July 6, 2023, in the journal Science. DOI: 10.1126/science.adg4521.

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• Yale School of Medicine
• Journal Science
• Understanding Aneuploidy
• CRISPR Technology Overview
• Targeted Cancer Therapies
• Previous Research on Oncogene Addiction
• Clinical Trials in Cancer Treatment
• Johns Hopkins School of Medicine
• Cold Spring Harbor Laboratory