Since late 2021, graduate student Justin Engel has tried to decipher why many cancers undergo massive rearrangements of chromosomes – a phenomenon that seems to drive malignancy and treatment resistance. Last August, he and his colleagues published a fascinating explanation in Cell: Cancer cells appear to hijack a genetic pathway involved in DNA repair to fuel their own genomic evolution.

As he continues to study this mechanism, Mr. Engel’s thoughtfully designed experiments and tireless efforts have earned him the 2025 Nominata Award, the highest honor bestowed on a UT Southwestern Graduate School of Biomedical Sciences student.

Mr. Engel is currently seeking postdoctoral fellowships to continue his cancer biology research.

The fourth-year student in the Cancer Biology Graduate Program has focused his research on identifying the genetic pathways driving chromothripsis – a process in which individual chromosomes undergo catastrophic shattering and error-prone reassembly in random order. This action generates complex genomic rearrangements that are observed in 30%-40% of all cancers and are commonly found in aggressive tumors such as sarcomas, glioblastomas, and pancreatic cancers.

Chromothripsis can occur when mitosis, the process of cell division, goes astray. Cells can mistakenly sort whole chromosomes or chromosome arms outside of the nucleus and into abnormal packages called micronuclei. Previous research led by Mr. Engel’s mentor, Peter Ly, Ph.D., Assistant Professor of Pathology and Cell Biology, demonstrated that these chromosomes in micronuclei eventually shatter into many pieces and reassemble in the incorrect order. But why these chromosomes shatter has been unknown.

Mr. Engel began exploring this question as a rotation student in the Ly Lab. He started his graduate work at UT Southwestern with skills that many of his fellow students had not yet developed – in between earning his undergraduate degree at the University of South Florida and before his graduate studies, Mr. Engel worked for three years as an industry scientist at Tango Therapeutics, a company that strives to develop new cancer treatments by exploring this disease’s genetic vulnerabilities.

“I already had a background in cancer biology. Since I started in the field, chromothripsis was something I always wanted to work on in some capacity,” Mr. Engel said.

Investigating chromothripsis

Using the gene-editing tool CRISPR, he inactivated genes in cells with micronuclei to find those that might play key roles in chromosome shattering. His hunt narrowed to a set of genes involved in the Fanconi anemia pathway – a DNA repair mechanism mutated in an eponymous genetic disease marked by severe anemia, bone marrow failure, cancer predisposition, and other congenital defects. When the researchers inactivated these genes, the chromosomes didn’t shatter.

Further research showed that unlike the chromosomes in the nucleus, those in micronuclei failed to properly replicate, spurring the Fanconi anemia pathway into action. As part of this DNA repair process, an enzyme complex then chops these chromosomes into pieces, causing the chromosome shattering characteristic of chromothripsis.

When these pieces are stitched back together in the incorrect order, they result in chromosome rearrangements that often inactivate genes meant to protect against cancer development, Mr. Engel explained. In addition, some pieces develop into a circular DNA structure called extrachromosomal DNA, or ecDNA, that gets amplified to a large number of copies, a process that can promote drug resistance.

The bigger picture

Dr. Ly noted that Mr. Engel’s dedication and critical thinking skills have been key to his success in the lab.

Peter Ly, Ph.D., Assistant Professor of Pathology and Cell Biology, (right) mentors Mr. Engel in his lab, investigating genetic pathways driving chromothripsis. The hope is that this research could eventually find a way to stop chromosome shattering and open a door to new cancer treatments.

“Justin’s work ethic and dedication to his research are truly impressive, but more importantly, he is a creative and independent thinker. He is constantly thinking deeply about the next experiment, the next big question, and how his research fits into the bigger picture in the field of cancer genome integrity,” said Dr. Ly, a member of the Cellular Networks in Cancer Research Program in the Harold C. Simmons Comprehensive Cancer Center.

Mr. Engel got a relatively late start in scientific discovery, he said, only joining a research lab for the first time near the end of his undergraduate career. Working with his mentor at the University of South Florida, Cecilia Nunes, Ph.D., he investigated biochemical pathways that lead to fruit and vegetable spoilage. After graduation, he joined the lab of another mentor at the same school, Huzefa Dungrawala, Ph.D., where he studied DNA replication in cells under stress until beginning his position at Tango Therapeutics in 2019.

Mr. Engel is continuing to search for other pathways involved in chromothripsis and ways to thwart this process to preserve chromosome integrity – work that could eventually lead to a new class of cancer treatments. After spending time both in industry and academia, he plans to remain in the academic setting and is currently seeking postdoctoral fellowships to continue his cancer biology research.

The Nominata was established in 1980 by the Graduate Student Organization to promote academic excellence and research achievement. The winner receives a monetary award and presents their research to the UT Southwestern community. As part of the University Lecture Series, Mr. Engel gave his Nominata lecture May 7 in the NG3 Auditorium.

Nominata finalist Devon Jeltema, Ph.D., a postdoctoral researcher, received a Dean’s Discretionary Award. Her work in the lab of Nan Yan, Ph.D., Professor of Immunology and Microbiology, involves studying interferon signaling – she recently published results of this work in the Journal of Experimental Medicine. In 2023, Dr. Jeltema received the William F. and Grace H. Kirkpatrick Award, which Mr. Engel won in 2024.