Sequencing Osteosarcoma’s Chromosomal Complexity

Isidro Cortés-Ciriano, PhD

In 2023, the OSI selected Dr. Cortés-Ciriano, along project co-lead University College London professor Adrienne Flanagan, MD, PhD, to receive a $499,914 grant that will fund their research into the causes and consequences of osteosarcoma’s genomic complexity. Using clinical tumor samples and innovative data analysis techniques, Dr. Cortés-Ciriano’s team at the European Molecular Biology Laboratory is working to identify the proteins affected by mutations in osteosarcoma that could then be targeted with immunotherapy or targeted therapy. Dr. Flanagan, a world renowned expert in bone cancer research, will conduct patient tumor sample selection, processing, and analysis.

What do we know so far about the osteosarcoma’s genetic makeup?

It is more complex than previously thought. We have long known that cancer is associated with genetic mutations — when rearrangements occur within specific segments of DNA. However, it was not until DNA sequencing was developed that we learned about chromothripsis, which is when one or multiple chromosomes become rearranged in a short period of time. Some cancers exhibit more chromothripsis than others. Of all cancers, osteosarcomas display some of the highest levels of chromothripsis. The DNA within osteosarcoma cells is scrambled massively. Other cancers that have similar levels of chromothripsis are, for example, brain, oesophageal, pancreatic, breast, and some lung cancers.

We have also learned that osteosarcoma tends to be highly heterogenous, meaning there can be varying amounts and types of chromothripsis depending on where in the tumor you look. This likely explains why immunotherapies and targeted therapies have not traditionally been successful at treating osteosarcoma. The treatments might kill a subset of cells in a tumor, but they are unlikely to kill all the cells because the cancer cells do not all have the same markers.

What does your osteosarcoma research focus on?

My interest is in trying to understand the mechanisms whereby a set of chromosomes that were perfectly fine can undergo such massive rearrangements that we end up with such a high level of chromosomal complexity.

How do you plan to explore osteosarcoma’s chromosomal complexity and understand what causes osteosarcoma?

Over the last few years, I have been working with University College London professor Adrienne Flanagan, who is a sarcoma pathologist with a very strong interest in bone cancer. She maintains a fantastic biobank with detailed clinical annotations, which is something that is usually lacking in larger scale genomics analyses.

A few years ago, we started to perform genome sequencing on multiple regions of each tumor to understand the mechanisms behind the onset of osteosarcoma. The idea is to characterize the diversity of mutations within a tumor. By analyzing different regions of a single tumor, we have been able to reconstruct its evolution. This is important, because it allows us to identify which molecular events or mutations mediate the transformation from a healthy cell into a cancer cell.

Now, with the funding from the OSI, what we want to understand is how the chromosomal alterations change which genes get turned on and off, including how the immune cells change and respond to the growth of cancer. Osteosarcomas are so complex, so diverse, that finding one drug to inhibit one protein is unlikely to be enough to kill the disease. We are hoping our work will be able to inform which areas of discovery are most promising, including which immunotherapy approaches, which harness the patient’s own immune system to kill the cancer cells, might be more effective against osteosarcoma. At the end of the day, we want what everyone wants — novel treatments that are more effective and less toxic.