Spatial Transcriptomic and Proteomic Analysis of Canine and Human Peripheral Nerve Sheath Tumors
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are rare but deadly cancers. Currently available drugs do not work, and surgical removal is often impossible due to the tumor location (typically major nerves) or the tumor has spread to other body parts. Due to these limitations, some studies have shown that the 5-year survival rate can be less than 25%. Therefore, the long-term goal of our research group is to use a deep understanding of the epigenetic modifications in MPNST to identify effective therapies. Epigenetic modifications refer to the external alterations in DNA to turn genes on or off. Epigenetic modifications alter the physical structure of DNA without changing the DNA sequence. Instead, they affect how cells read genes. Although we have defined some of the epigenetic drivers in MPNSTs, their rarity presents challenges to performing informative clinical trials. Another challenge clinicians face in treating MPNSTs is the high heterogeneity amongst tumors, which can cause different responses to treatment and even resistance. Further, the inability of laboratory animal models, such as mice, to fully recapitulate the complex genetic, biological, and environmental factors driving complex diseases such as MPNST has impeded the identification of effective therapies. To address this problem, we propose to use naturally developing cancers in companion animals as a model that can support research efforts that produce meaningful results in people. We hypothesize that human and canine peripheral nerve sheath tumors (PNSTs) have similar specialized tumor compartments (distinct three-dimensional 3D areas within the tumor, as shown by the uneven loss of the epigenetic mark, H3K27me3) that contribute to specific expression signatures that promote tumor growth. We will test our hypothesis using digital spatial profiling, a method that combines molecular signatures from gene and protein expression with high-resolution imaging to visualize the expression patterns for an image of a tumor. This study addresses all the Fiscal Year 2022 Rare Cancer Research Program Focus Areas: (1) Biology and Etiology, by identifying disease-defining molecular pathways conserved across mammalian species; (2) Research Model, by validating canine PNSTs as a rare tumor specific model that can support clinical trial readiness; and (3) Therapy, by identifying of tumorigenic pathways to target with novel therapeutic strategies. The objective of this study is to perform digital spatial profiling of genes and proteins in canine and human MPNSTs to understand the common PNST drivers across species. The rationale is that identifying the gene and protein expression differences shared between dogs and humans in a spatial context will: (1) identify novel molecular signatures and cellular interactions driving MPNST progression, (2) facilitate the identification of targets for the treatment of MPNST, and (3) expedite canine clinical trials that can then inform human trials. The study will map specific molecules (genes and proteins) to where they are expressed in canine and human PNSTs images. The translational applicability of the research is that: (1) integrating the gene expression (transcriptomics) with protein expression (proteomics) in 3D can bridge the gap in our understanding of the molecular mechanisms driving MPNST progression; and (2) it will identify the contexts in which pharmacologic inhibition of an epigenetic defect will be an effective treatment strategy for MPNSTs. Our studies will have a positive impact by establishing the canine PNST as a powerful research model of MPNST. The implications of this are that the high incidence of the disease in dogs can inform future clinical trials. Consequently, the knowledge gained from this work could expedite appropriate treatment, and therefore, potentially advancing patient care and improving patient survival. The study addresses the clinical need for effective treat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310978
Entities
People
- Keila E Torres
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army