NF1-Associated Peripheral Nerve Sheath Tumors at Single-Cell Resolution: Heterogeneity, Tumor Growth, and Malignant Progression
Abstract
One of the major clinical complications of persons with Neurofibromatosis type 1 (NF1) is the generation of tumors of the peripheral nervous system (PNS), such as plexiform neurofibromas (pNFs). These tumors initiate before birth, forming big benign lesions that grow along large nerves and disorganize the tissue surrounding it. pNFs may originate inside the body or externally, affect about 50% of NF1 individuals and may cause a great impact on their quality of life. In addition, these tumors in certain cases may progress towards a malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma type. Despite the great advances in the understanding of how these tumors form, the reality is that, today, we still do not have the necessary tools to cure most of them. There must be a fundamental aspect of these benign and malignant tumor cells that we still do not know and that impedes the discovery of effective drugs. Current molecular and cellular technology has evolved so that it makes possible the analysis of the genetic content of individual cells. Thus, today we can dissociate fresh tumors and analyze the content of thousands of individual tumor cells. With this single cell analysis, we can have a very fine resolution of the cellular composition and cellular heterogeneity of tumors. We have started to analyze different pNFs with these single cell techniques and realized that, in addition to the known different cell types composing pNFs, some of them seem to be subdivided in different cell categories. For instance, two of the main cell types forming pNFs are Schwann cells (SCs), the cells that wrap and protect nerve axons, and specialized nerve fibroblasts (FB). Within the SC component, we identified SCs that look like developing SCs (less differentiated or precursor cells) and other SCs that look more mature (committed to SCs). We also identified different subpopulations in the FB component of pNFs. This diversity within pNF cell type components was previously unnoticed or at least not well characterized. Since less differentiated cells could have properties similar to tissue stem cells (cells that regenerate tissues), we are interested in investigating the biological properties of these cell subpopulations, their importance for pNF growth, on tumor progression and in the response to treatment. To do so, we have planned to create a cell map of each tumor type (e.g., plexiform neurofibromas, MPNSTs) by combining data obtained applying different single cell technologies. We conceive these single-cell resolution tumor maps as a resource that will be shared with the whole scientific NF community, which could grow also with contributions of the different laboratories making use of the resource. These single-cell resolution maps will provide a detailed description and genetic status of all cell types and cell subpopulations composing these tumors and will help us to identify a way to separate these subpopulations. Then we will be able to study their properties and functions. If we are able to uncover the role of the different subpopulations of cells within these tumors, we will better understand tumor growth and malignant progression. In addition, we will be able to analyze, using faithful tumor models, tumor response to different drug treatments, not only by analyzing a reduction in tumor volume or mass, but by analyzing the impact of treatment in each of the different cell subpopulations in response to treatment. In this way, we will be able to look for effective drugs with a different perspective, since we will be interested in those drugs targeting particular subpopulations of cells that we understand are important for tumor growth, maintenance, and progression. PNS tumors affect most NF1 patients, so any step in the direction of identifying more effective agents would represent a big impact on the quality of life of many people. The proposed work will generate a useful resource for th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110483
Entities
People
- Eduard Serra
Organizations
- United States Army