Functional Heterogeneity in MPNSTs and Plexiform Neurofibromas
Abstract
Malignant peripheral nerve sheath tumors (MPNST) and plexiform neurofibromas (PN) are frequent tumors in the setting of NF1. About 25% of NF1 patients develop plexiform tumors and about 10%-15% of them develop MPNST. Clinically, both tumor types are extremely difficult to treat successfully. All evidence to date points to the fact that malignant MPNSTs arise from the benign plexiform neurofibromas. It is also clear that these tumors are complex (heterogeneous) in that they contain many cell types that likely interact in some way to sustain tumor growth. One useful method to study tumors is by placing the cells into tissue culture or by transplanting them into mice. For MPNST and plexiform neurofibroma, such methods have been unavailable, thus limiting progress. In fact, the field relies on a very few MPNST cell lines to study disease mechanisms. For many reasons, including the difficulty in establishing these rare cell lines, many believe that these few cell lines may be aberrant and not truly representative of the original tumors. Another powerful way of studying neurofibromatosis has been the development and use of genetic mouse models that recapitulate aspects of the disease. My laboratory has pioneered this approach to study NF1. Recently, we have successfully developed tissue culture protocols that allow us to readily culture MPNST and PN. In addition, we can reintroduce the cells into mice and reproduce both tumor types. This is a significant advancement in the field because it strongly suggests that our primary cultures closely resemble the original tumors. Therefore now, coupled with our mouse models, we propose to address the functional significance of tumor heterogeneity. Why are these tumors so complex and what is the meaning of the complexity? In fact, we have generated substantial evidence that leads us to believe that there is a specific and unique cell type within these tumors that we call a "cancer stem cell." We believe the cancer stem cell is the source of tumor growth and that it produces the cells responsible for tumor expansion and, in the case of MPNST, metastasis. We believe these cancer stem cells are responsible for drug resistance. Taking our unique set of genetic and tissue culture tools, we propose to definitively identify and, importantly, isolate the cancer stem cells for MPNST and PN. If our ideas prove correct, the ability to study cancer stem cells in isolation may provide us with new information and insight about how to effectively neutralize them. Without the ability to isolate them, these cells would be like needles in a haystack (the tumor) and therefore exceedingly difficult to determine how different therapies affect them. As our progress emerges in the project, we will make efforts to begin to translate the information and technology to patient-derived material. We anticipate this will occur towards the end of the current proposed funding period. Our expected findings would reorient heretofore unsuccessful therapeutic approaches to the targeting of cancer stem cells as a means of impeding tumor growth.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610186
Entities
People
- Luis F. Parada
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army