If a cancer cell were an enemy spaceship in a science fiction movie, defeating it would be pretty easy: Just look for the big red self-destruct button and manipulate someone inside into pressing it.
In a sense, this strategy underlies many existing cancer treatments. Though cancer cells don’t technically have a big red button, all of our cells have a built-in self-destruct mechanism. Many cancer treatments, from chemotherapy to radiation to newer targeted immunotherapies, are simply different ways of making a cancer cell experience enough stress to initiate its own self-destruction via this natural process that exists in all the body’s cells.
“If I were a cancer cell, and I wanted to become resistant to treatment, and I wanted to have a life in a setting of abundant stress, I would look for opportunities in which I could change my threshold for how much stress it takes to kill me,” said Michael Hogarty, MD, a pediatric oncologist at Children’s Hospital of Philadelphia and associate professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.
If cancer cells were to raise their stress threshold, they could become broadly resistant to any treatment through a strategy akin to putting ear plugs on the operator of the big red button: No matter where the order to self-destruct comes from, he can’t hear it. Scientists have indeed found repeatedly in many cancers that, after treatment and relapse, no matter what kind of therapy the cancer was initially exposed to, it becomes resistant to most or all other treatment approaches. But early investigations into this phenomenon of broad cancer resistance fell short and largely fell out of favor.
In a new project, Dr. Hogarty and colleagues are focusing on organelles called mitochondria that are in charge of initiating cellular self-destruction. They are seeking ways to keep the big-red-button strategy working even in cancers that have developed broad resistance to therapy.
“Mitochondria are the hub for integrating all these stress signals and regulating programmed cell death, or apoptosis, apart from their role in producing energy,” said Jorida Coku, a cancer biology doctoral student in Dr. Hogarty’s lab who leads the project. “They integrate all these signals from within the cell, such as stress signals resulting from DNA damage caused by chemotherapy or radiation.”
She is building on preliminary work that pointed to a hypothesis about how mitochondrial signaling may be altered in most or all cancer-resistant cells. Several years ago, Dr. Hogarty began by extracting mitochondrial-associated membranes from numerous cancer cell samples in the lab. After exposing them to varied concentrations of different stress signaling molecules, he measured whether the mitochondria then released the characteristic molecular signals of apoptosis.
“That’s a very measurable thing in the mitochondria,” Dr. Hogarty said. “They basically open up their pores and dump all of these death proteins. It’s definitely not like an, ‘Oops, I didn’t mean to do that, can I stay alive?’ It’s a point of no return.”
Through that work, he found three distinct fingerprints or profiles of how different cancer cells’ mitochondria responded to stressors. All the mitochondria that ultimately responded to a stressor with that “death protein dump” did so in one of two distinct patterns. The key finding for the current project was that a third profile comprised all the mitochondria that would not respond to any stress signal at any biologically plausible concentration. Although the signals were shouting to the mitochondria at high volume, they did not initiate the self-destruct sequence. And, it turned out, all of the samples in this third group came from tumors in children who had undergone treatment for cancer and then relapsed.
“It was one of those ‘aha’ moments when you say, I think we’re looking at the whole phenotype of resistance right here,” he said. “It’s at the mitochondria.”
Coku picked up the then-dormant project when she joined Dr. Hogarty’s lab in January 2015 and is now testing the specific hypothesis that the mechanism of this broad resistance phenotype involves the loss of physical tethers connecting mitochondria to another organelle, the endoplasmic reticulum (ER). The ER is an important source of calcium signals to mitochondria that are involved in triggering apoptosis, as well as other signals such as lipid signals.
Although traditional textbook diagrams of a cell show mitochondria floating free within the cell, they are actually physically connected via several types of molecular bridges or tethers to the ER that are pathways for delivering those signals. Dr. Hogarty hypothesized that this tethering was a key factor in cancer therapy resistance based on multiple lines of evidence in his preliminary studies of in vitro mitochondrial membranes which were variably connected to ER membranes in his samples.
Coku’s experiments involve cutting the tethers between mitochondria and ER in therapy-sensitive tumor samples, re-attaching tethers in therapy-resistant tumor samples, and measuring the results. She is also working to elucidate more of the mechanism of how a loss of tethering could change calcium signaling to produce the resistant cancer phenotype, which could lead to finding targets for intervention. This could also allow researchers to develop tools to measure the degree of linkage between ER and mitochondria in patients’ tumors as a proxy for their sensitivity to drugs.
“And, moreover, we could investigate drugs or interventions that might not look like cancer drugs by themselves,” Dr. Hogarty said. “They might be completely incapable of killing a tumor, but by doing something to restore this ER-mitochondrial function in a relapsed cancer, they might make a difference between not responding to the drugs a clinician would choose, and responding again, which would be fabulous.”
An added potential implication of this work is for improved design of clinical trials of investigative cancer treatments, which, for ethical reasons, only enroll patients after relapse when no proven treatment remains. If these patients’ tumors show a phenotype of broad therapy resistance, then most investigative new treatments would seem doomed to fail. Future trial designs might take this factor into account and seek additional or different molecular indicators of a new drug’s activity in tumors, even if it cannot shrink tumors that already have broad resistance, Dr. Hogarty suggested.
“We want to show that this is a model that explains broad therapy resistance in various types of cancers, not only in pediatric cancer, but even in adult cancer,” said Coku, whose master’s thesis research project prior to coming to Penn involved investigating the increased crosstalk between mitochondria and the ER in the context of Alzheimer’s disease — the opposite effect of that hypothesized to have a role in cancer treatment resistance. She noted that findings about these mechanisms in cancer might also inform studies of neurodegenerative disorders.
The team recently received grant support from the National Cancer Institute for the project, and they expect to submit their first manuscript soon.