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.
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.