Identification of Cellular Heterogeneity and Oncogenic Networks in MPNST by Single-Cell Transcriptomics and Epigenomics for Targeted Therapy
Abstract
Neurofibromatosis type I (NF1) affects at least 100,000 people in the United States and 2 million individuals worldwide. One major burden for these patients are the growth of peripheral nerve tumors. Although benign in nature, in some cases, the slowly growing NF1-mutated tumors deeply seated in branches of larger nerves can lead to cases of runaway cell growth, creating very large and sometimes medically problematic plexiform tumors that can turn into malignant peripheral nerve sheath tumors (MPNSTs). How benign neurofibromas become cancerous MPNSTs is still a puzzle. MPNSTs are very aggressive tumors started from a specialized cell called a Schwann cell in the nerves throughout our bodies from the skin to and around the organs. They typically present as fast-growing masses in nerves, causing pain and disability, and are a major cause of death for NF1 patients. One of the promising ways to treat MPNST is to target the specific signaling pathways that cause tumor formation and progression and to discover potential drug targets against tumor growth. To achieve this, it is important to learn about what causes normal Schwann cells to become cancer cells leading to MPNST. Our recent study shows that a pathway, called HIPPO, goes awry in MPNST tumors but not in benign NF, indicating that abnormal HIPPO activity may contribute to benign-to-malignant transition of NF. We have generated a set of mice with HIPPO pathway malfunction in Schwann cells. Typically, 100% of these mice develop malignant nerve sheath tumors. The tumors in these mice are very similar to those seen in human MPNST patients, both in children and adults. We therefore can use these mice to learn about MPNST biology. In NF and MPNST, Schwann cells, due to mutations, no longer behave like normal cells, but often take up other identities and transition into cancerous cells. How they do that and what the process of malignancy transition is largely a mystery. Moreover, extra cells normally not present in healthy tissues, such as immune cells, are abundant in tumors. All these cells interact with the tumor just as the tumor can interact with these surrounding cells. This creates a highly dynamic ecosystem that is constantly changing to serve the needs of the tumor. Cancer behaviors, including how a tumor grows, spreads, and resists drugs, critically depend on how tumor cells talk among themselves and to the surrounding cells through a “signal sending-receiving” relationship. To understand what signal is exchanged between individual cells within a tumor, we use single-cell transcriptomics and epigenomics that enable us to detect global gene expression patterns of individual cells and which gene networks control these patterns at very high resolution. Single-cell data can tell us what cell populations are within a tumor and how they talk to one another to make the tumor grow bigger and deadlier. One way tumor cells become more powerful is to escape surveillance by immune T cells, which act like “police” cells in the body. We can develop drugs to make cancer cells more visible to the immune system. This will open new opportunities for finding out how tumor microenvironment may cause transition of benign NF into MPNST and developing better tools to specifically attack the tumor. MPNSTs are often resistant to treatments like chemo and radiation therapy. None of the clinical trials aimed at inhibiting NF1-regulated RAS signaling have yet shown benefit in MPNST patients. We will study how gene expression changes are controlled by RNA-sequencing and epigenomics in RAS-MEK inhibitor-resistant MPNST in xenograft models. In principle, this research emerges as a new paradigm in NF and MPNST research and will help us understand how benign NFs are transformed into malignant tumors, as well as inform the next steps of more rational therapy design.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010443
Entities
People
- Lai Man Wu
Organizations
- United States Army