Loss of ER-mitochondria contacts drives therapy resistance in neuroblastoma
Many high-risk childhood cancers are lethal because they become resistant to available treatments. The paradox is that these cancers endure the most stress of any cells of the body: growing where nutrients are scarce and spreading to inhospitable body parts all create stress signals that ought to kill the cancer cells. Further, the treatments we give are chosen for their potency at causing more stress. Work from our lab shows that these cancers don’t survive because they can’t create stress signals, they survive because they develop ways to keep the stress signals from killing them. It is essential we understand this process better since resistance to our therapies is the major cause of childhood cancer death. We studied neuroblastoma cell mitochondria (the organelle that senses stress and makes live-or-die decisions) and showed resistant cell mitochondria aren’t as sensitive to stress signals as non-resistant neuroblastoma mitochondria. We have shown this is because they have lost an essential connection with another organelle called the ER. Loss of ER-to-mitochondria connections makes the mitochondria resistant to stress. One key function of these connections is to transfer lipids (specialized fats) to the mitochondria, and work from our laboratory and many others suggests this loss of lipids may be responsible for the cell’s ability to survive stress. How changes in lipids within mitochondria have this effect will be explored in greater detail in this work, and our results will enable tests that identify or predict resistance and also uncover novel strategies to counteract this resistance.
Project Goals:
We need to understand how cancers resist the stress they encounter as they spread in the body, and how they resist the stress caused by our diverse cancer treatments. This is critical because cancer cells that become resistant to these stress signals are responsible for most childhood cancer deaths. This is a fundamental challenge. Our work shows that tumor cells do indeed have an abundance of stress signals within them, yet they are resistant to cancer treatments because their mitochondria are unusually resistant to stress signals. Mitochondria are the organelles in the cell that collect stress signals and decide whether a cell should remain alive or die. We found that the mitochondria that are resistant to stress signals have lost essential connections to another cell organelle called the endoplasmic reticulum, or ER. In a normal cell, the ER and mitochondria are highly connected. The ER delivers essential metabolites to the mitochondria through these connections. Our work here will investigate how the loss of lipids (a key mitochondria metabolite delivered from the ER) effects their response to stress. We will catalog the lipids in sensitive and resistant cancer cell mitochondria and show how the absence of critical lipids affects their function. We will also prove using complementary approaches that perturbing these lipids (either increasing or decreasing them) can toggle cancer cells from more to less resistant to our cancer therapies. This improved understanding of how cancer cells evade our treatments will have a profound impact in our ability to treat them successfully.
Project Update 2024:
Most childhood cancer deaths are caused by the relentless growth of tumor cells that have become resistant to available treatments. Our understanding of what drives this broad treatment resistance is limited, but we have discovered that neuroblastoma cells taken from children after they have relapsed do not respond to stress normally. The cells are much less likely to die from chemotherapy and radiotherapy than are neuroblastoma cells taken from children at the time of diagnosis. We find that these resistant cells have made changes in the way they organize their mitochondria. Mitochondria are the small organelles in a cell that are responsible for killing the cell when strong stress signals are received. We found that resistant tumor cells have disconnected their mitochondria from an important helper organelle called the ER. The ER and mitochondria are usually intimately connected at multiple places, and these contacts allow the ER to deliver the lipids (fats) to the mitochondria that it needs to function normally. Not only do resistant cells have fewer contacts between their ER and mitochondria, the mitochondria themselves have changes in their lipid content and aren’t able to respond to stress normally. We have explored how these changes affect the cells, how we can measure this process, and what approaches we might take to restore their normal functioning. If we can do this, the cells would no longer remain resistant to our treatments. Much of this work involves the biology of how cells utilize fats called lipids, so much of our work tried to measure the way lipids are moved in the cancer cells and what effect they have on drug responses. This remains a difficult problem, but we also strongly believe it is a solvable problem.
