Although cancer is initiated by mutations in the DNA of individual cells, cancer maintenance and progression also depend on cancer cells' ability to hijack the activities of non-cancer cells in their local environment. Over the past decade, interactions between cancer cells and neurons in the central and peripheral nervous systems have been discovered to be particularly important for cancers to grow aggressively, disseminate through the body, and become insensitive to standard treatments. These interactions were initially studied in glioma, the most common type of malignant brain tumor, due to the prevalence of neurons in these tumors. Remarkably, glioma cells and neurons communicate with on...

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Although cancer is initiated by mutations in the DNA of individual cells, cancer maintenance and progression also depend on cancer cells' ability to hijack the activities of non-cancer cells in their local environment. Over the past decade, interactions between cancer cells and neurons in the central and peripheral nervous systems have been discovered to be particularly important for cancers to grow aggressively, disseminate through the body, and become insensitive to standard treatments. These interactions were initially studied in glioma, the most common type of malignant brain tumor, due to the prevalence of neurons in these tumors. Remarkably, glioma cells and neurons communicate with one another continuously by releasing small molecules and short proteins that bind to receptors on the cell surface. Moreover, glioma cells can form physical connections, or synapses, with neurons that allow them to integrate into electrical networks in the brain. Through these interactions, glioma cells receive signals from activated neurons that instruct them to grow and divide. Glioma cells trigger the activation of neurons in their local environment to increase the intensity of these neuron-derived signals, although the specific ways that glioma cells promote the activation of neurons is poorly understood. Studies of neuron-cancer interactions have also included cancers that form outside of the brain, including prostate and pancreatic cancers. These cancers rely on interactions with neurons from the peripheral nervous system to promote their growth. However, we still know relatively little about the ways that cancer cells communicate with neurons, particularly in pediatric cancers. Therefore, we crafted our research program to answer three fundamental questions across three pediatric cancers. First, what are the molecules that cancer cells release to promote nerve growth? Second, what signals do neurons send to cancer cells that promote tumor growth and therapy resistance? Third, how might we develop therapies that disrupt neuron-cancer cell communication? Our research focuses on three types of pediatric cancer for which new biological insights and therapies are desperately needed, including pediatric leukemia, osteosarcoma, and high-grade glioma. Pediatric leukemias are blood cancers that account for 28% of all cancer diagnoses in children. The most intractable form, acute myeloid leukemia, has a 5-year survival rate of only 65-70%. Pediatric osteosarcomas (tumors that form in the bone) and high-grade gliomas (the most aggressive form of brain cancer) are less common but at least as deadly, with 5-year survival rates of 68% and less than 10%, respectively. Our ultimate goal is to improve our understanding of how neurons and cancer cells communicate in each of these cancers and to use these insights to develop new therapies. We propose to conduct three research projects integrated by an Administrative Core. Project 1 is led by Dr. Sean Morrison, a stem cell and cancer biologist who discovered cells and mechanisms in the bone marrow that enable the maintenance of blood-forming stem cells and blood cell production. His laboratory recently discovered mechanisms by which nerves promote bone marrow regeneration after radiation or chemotherapy. Their group will now explore the implications of these mechanisms for leukemia growth and therapy resistance. Project 2 is led by Dr. Benjamin Levi, a surgeon-scientist who is a leader in the field of bone regeneration. He has deep expertise in aberrant bone growth mechanisms that occur after trauma that he will apply to understand the role of peripheral nerves in the regulation of pediatric osteosarcoma growth and progression. Project 3 is led by Dr. Samuel McBrayer, an expert in glioma biology and cancer metabolism whose work has led to two clinical trials of new therapies for brain cancer, including one that is ongoing and one that is slated to begin later this year. His laboratory will investigate the role of a novel metabolite they found enriched in adolescent gliomas and that they hypothesize regulates neuron-brain tumor communication. Dr. Morrison will also lead the Administrative Core that will manage all aspects of the MIRA consortium, foster synergy among projects, and convene a scientific advisory board. Project 1 is based on the Morrison laboratory's discovery that certain non-cancerous cells that reside in the bone marrow, called Leptin receptor-expressing (LepR+) stromal cells, are responsible for secreting a protein called nerve growth factor (NGF) that maintains nerve fibers in the bone marrow. These nerve fibers are essential for the regeneration of blood cell production after bone marrow damage by radiation or chemotherapy. They do this by releasing neurotransmitters (like adrenaline) that activate ß adrenergic receptor signaling in the LepR+ cells, increasing the production of growth factors by LepR+ cells that promote bone marrow regeneration. Because blood-forming stem cells and leukemia cells respond to many of the same signals, and leukemia cells often grow in the bone marrow, the Morrison laboratory proposes to examine how nerves regulate pediatric leukemia progression and response to therapy. They will test if the loss of nerve fibers or ß adrenergic receptor signaling in the bone marrow alters acute leukemia progression or the response of leukemia cells to standard therapies. They will also test if "beta blockers", drugs that act by inhibiting ß adrenergic receptor signaling and are widely used to treat high blood pressure and heart conditions, affect leukemia progression or engraftment after bone marrow transplants (a therapy commonly used to treat leukemia). They will test these effects on bone marrow transplantation in mice and by comparing outcomes after bone marrow transplants in people who were, or were not, taking beta blockers at the time of transplantation. The research proposed in Project 2 will build on the Levi laboratory's discovery that osteosarcoma cells as well as non-cancerous cells that surround blood vessels in bone release NGF to stimulate sensory nerve growth into tumors. Their laboratory has shown that inhibiting nerve growth undermines osteosarcoma growth, underscoring the importance of figuring out how nerve cells regulate tumor growth. To address this issue, they will first define the contributions of osteosarcoma cells and non-cancerous cells around blood vessels to nerve growth. Second, they will test if nerves promote osteosarcoma growth by increasing Transforming Growth Factor ß (TGFß ) signaling in osteosarcoma cells. TGFß is a growth factor that promotes proliferation and migration in many kinds of cells. Third, they will use drugs that are FDA approved or currently in clinical testing to inhibit nerve-cancer cell signaling in osteosarcoma to assess the impact on cancer growth and pain caused by the cancer. The research proposed in Project 3 by the McBrayer laboratory will tackle a key question pertaining to high-grade gliomas that form in adolescents: how do cancer cells signal to neurons to increase their activity? To address this question, the McBrayer laboratory quantified hundreds of metabolites in dozens of patient-derived brain tissue samples. They identified one metabolite that is enriched in adolescent high-grade gliomas and known to activate neurons in a rare metabolic disease. Therefore, the McBrayer laboratory will test the idea that adolescent high-grade gliomas hijack local neurons by releasing a metabolite that increases their activity. First, they will delineate the mechanism by which this metabolite accumulates in gliomas. Second, they will perform electrical activity studies of the brain to understand how elevated levels of this metabolite affect neurons. Third, they will suppress this metabolite in mouse models of pediatric high-grade glioma and examine the impact on brain tumor growth, neuron-glioma signaling, and cancer metabolism. Our projects will provide unprecedented insights into the signals that neurons and cancer cells send one another and how these signals contribute to pediatric cancer growth in the nerve-rich bone and brain environments. By working collaboratively across several pediatric cancers, our laboratories will identify shared and disease-specific ways that neurons and cancer cells interact. Historically, features that are shared by many cancers mark some of the most important processes that cancer cells rely on for their survival. Therefore, collective insights from our group will be used to identify common neuron-cancer communication mechanisms and prioritize targeting these mechanisms in pre-clinical therapeutic studies. In pediatric leukemia, our findings could prompt rapid clinical trials of drugs that alter the signaling of ß adrenergic receptors, given that they are already approved for clinical use. These drugs could be used to inhibit leukemia progression or accelerate recovery after bone marrow transplantation. In pediatric osteosarcoma, our work could reveal new therapeutic targets and drugs in clinical development that could inhibit neuron-osteosarcoma communication. In pediatric high-grade gliomas, our proposed research may bridge our knowledge of metabolic and neuronal dysfunction in brain cancer, nominate a new target for therapy, and motivate the development of drugs that inhibit this target. Finally, treatment strategies developed for osteosarcoma and glioma could have added usefulness in reducing tumor-related pain and seizures, thereby improving the quality of life for children living with these debilitating cancers.

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