Can the guardian of the genome protect against chromosome abnormalities in cancer?

Our DNA carries the instructions that allow our cells to function properly. During cell division, this DNA, packaged in chromosomes, is carefully copied and passed on to daughter cells. Errors during this process can cause cells to receive too many or too few chromosomes, resulting in a condition called aneuploidy. This chromosome imbalance is frequently seen in cancer cells.

Security system

Cells are equipped with a security system to detect and eliminate aneuploid cells. Understanding how these systems work, and why they sometimes fail, is crucial for understanding cancer development. One key player in this cellular security system is the protein p53, nicknamed the ‘guardian of the genome’. When cells experience stress or damage, p53 can stop cell division and trigger cell death.

“The protein p53 is thought to protect us from DNA-related stresses, such as aneuploidy, by eliminating affected cells,” Joana explains. “Since p53 is often mutated in cancers, researchers have long believed that p53 acts as a key defense against aneuploidy.” In her thesis, Joana set out to carefully study the assumption that loss of p53 is related to aneuploidy in cancer.

No direct link

She first analyzed data from The Cancer Genome Atlas, a large public database created to trace genetic changes across many cancer types. By examining genome data obtained from tumors across 31 different cancer types, she found that inactivation of p53 is not directly linked to cancer aneuploidy. On the contrary: many cancers accumulate high levels of aneuploidy even when p53 still functional.

Context-dependent role for p53

To test this experimentally, Joana optimized a molecular biology tool which allowed her to  track p53 activity in live cells using fluorescence microscopy. By inducing aneuploidy, she could directly observe how cells responded. While p53 was sometimes activated following chromosome segregation errors, the response was inconsistent and often delayed by more than 24 hours. This delay suggests that activation of p53 is not directly triggered by the chromosome segregation errors, but rather by their downstream consequences.

“We observed that cells with working p53 can tolerate experimentally-induced aneuploidy and some aneuploid cells can continue to grow without activating p53,” Joana says. Based on her findings, Joana concludes that p53 is not a universal safeguard against aneuploidy. Instead, its role is highly context-dependent. Some aneuploid cells activate p53, while others do not. She stresses: “These results highlight the importance of considering factors such as tissue type and type of aneuploidy when studying the response to aneuploidy.”

Accounting for diversity

By refining experimental tools used to study the role of p53 in response to aneuploidy, Joana’s work may help guide future research on how cancers develop and how they might be treated in the future. “It’s important to take biological diversity into account when designing experiments, rather than relying on a small number of commonly used model systems,” she advices.

Lost and found

For Joana, the PhD journey was one of discovery, not only scientifically, but also personally. Despite the time pressure, she learned to embrace the constant change and growth that occurred to her as a scientist and as herself. “I definitely got lost and found many times, but I am who I am today because of this journey, and I am very grateful for everything it gave me,” Joana reflects.

Beyond the science, one of her proudest achievements was founding the Green Team, a committee dedicated to making the Hubrecht Institute more environmentally friendly. To new PhD students, Joana offers this advice: “If you like doing science, go for it! Choose a topic your passionate about, a present and supportive mentor, and a good lab environment. A good support system, curiosity and hard-work will take you through it!”