A moment can change everything.
Growing up, Dr. Cyrus Ghajar had always been interested in biology and hoped to find a career that allowed him to help others. But when he was getting ready to enter the University of California, Berkeley, and quickly scanned a list of potential majors, he didn’t see biology listed in the “B” section. He chose bioengineering as a second-best.
“It’s funny how a split-second decision ends up impacting the rest of your life,” says Ghajar.
Ghajar traces the origin of his career as a cancer researcher back to that “whimsical” decision, which led him to approach the problem of cancer recurrence from an unexpected angle — one which could help stop cancer cells that have spread — but are dormant — from reactivating.
Even successful cancer treatment can be undone by a few lingering tumor cells. These cells may break away as the tumor forms and find new homes in distant organs, where they can lie quiet for months, years or decades before rousing and sparking growth of new tumors. The result can be deadly.
Ghajar, a researcher in Fred Hutch’s Public Health Sciences Division and holder of the Peter S. Lefkarites Memorial Endowed Chair, has long been fascinated by this phenomenon. His laboratory studies exactly what it is about these distant locales that keeps tumor cells dormant for so long — and what changes in those surroundings prompt these far-flung tumor cells to resume growth.
“In many patients, we have a unique window of opportunity to do something about these seeds of metastasis before they sprout. We have to figure out a way to take advantage of it,” says Ghajar.
Cancer cells “lose their bully mentality” when they leave the original tumor and enter a new environment, he notes. Rather than continuing to divide, tumor cells lie low, heeding the influence of molecules in their new locale that restrain their growth. Ghajar is working to identify these molecules and understand how they influence dispersed tumor cells, knowledge that could be harnessed to prevent cancer recurrence.
Ghajar brings his bioengineering background to bear on the problem, including formative training he received as a postdoctoral fellow with Dr. Mina Bissell at Lawrence Berkeley National Laboratory, where he examined blood vessel formation in tumors. Bissell, “who’s all about breaking dogma,” says Ghajar, encouraged her mentee to turn the topic on its head. “People had studied how tissue environments promote metastasis, but there were few studies on the converse: how tissues stop tumor cells from growing and put them to sleep,” Ghajar remembers.
“In many patients, we have a unique window of opportunity to do something about these seeds of metastasis before they sprout. We have to figure out a way to take advantage of it.”
Using a preclinical model of breast cancer, he examined different organs to see where newly arrived breast cancer cells tended to reside. He discovered that they live on or near the body’s tiniest blood vessels, and that these capillaries release molecules that dampen cancer cells’ aggressive growth — potentially for years or decades. But when change prompted the capillaries themselves to grow, Ghajar found that the metastatic cells grew as well. He showed that signals from growing blood vessels not only fail to suppress tumor cells, they actually rekindle life-threatening metastases.
Drawing on his bioengineering training, he has developed 3-D lab-based breast tumor models that give researchers an easily manipulated system to examine how various environments influence tumor cells.
Ghajar is using these models to determine whether a common mechanism governs the growth of tumor cells after they spread or whether the pathways are unique to the specific organ in which the cells settle. This is the first step toward identifying potential therapeutic targets, he explains. In addition, he’s beginning to examine another pressing question: how these slumbering tumor cells resist chemotherapy that has cured a patient of their initial tumor.
Answering these questions will allow researchers to nip metastases in the bud and provide lasting cures to cancer patients.
— By Sabrina Richards, updated April 21, 2023