Utilization of a Novel Genetically Engineered Mouse Model to Elucidate the Roles of the Extracellular Matrix in Epithelioid Hemangioendothelioma Progression
Abstract
Epithelioid hemangioendothelioma (EHE) is a rare cancer that can either remain dormant or unexpectedly become aggressive. As we have no effective treatments, patients with aggressive disease have poor outcomes. EHE disproportionately affects women. It is characterized by a single unusual chromosomal exchange. Being a rare cancer, adequate patient samples can be difficult to obtain. No cell or animal models of human EHE have been available, severely limiting researchers’ ability to test hypotheses or develop treatments. Therefore, little is known about the molecular events that cause this disease. In this application, we aim to develop models that recapitulate human EHE and identify the proteins that can be targeted for treatment. We hypothesize overall that the protein-rich fibrous mesh called “matrix” that surrounds the tumor cells provides a nurturing environment that facilitates tumor growth and spread. We will test this hypothesis by modeling EHE to identify disease-defining components of the matrix. We reported that in EHE, the unusual chromosomal exchange fuses two genes named TAZ and CAMTA1. We hypothesized that this TAZ-CAMTA1 (TC) fusion drives EHE, so we created an innovative mouse model (TC mouse) that expresses the fusion as in human EHE. TC mice developed tumors, and when they are observed under the microscope, we see elongated tumor cells sitting in an abundant blue-gray, protein-rich matrix much like human EHE. Thus, our mouse model recapitulates human EHE and can be used to understand the human disease. To understand how TC causes EHE, in Aim 1, we will use our mouse model to generate tumor cell lines and other mouse models that we and others can use to rigorously test various hypotheses. These models are absolutely critical to advancing the knowledge of EHE and evaluating potential treatment options. We found that the composition of TC mouse and human EHE tumors are remarkably similar at the RNA level. To identify what makes EHE unique, we compared EHE with similar cancer types. Our analysis shows that EHE tumor is unique in that matrix components are enriched, which is consistent with our microscopy observations. We identified that one of the genes turned on by TC, connective tissue growth factor (CTGF), a component of the EHE tumor matrix is critical for tumor cell survival. In Aim 2, we will investigate how CTGF signals to tumor cells to allow them to survive. Using a mouse model, we will also probe whether stopping CTGF signaling with drugs, already approved by the FDA, reduces tumor burden. If successful, in the future, these drugs may be used to treat EHE patients. Others have shown that CTGF stimulates cells to secrete some of the matrix components, so using tumors from patients with EHE, we will investigate whether CTGF levels correlate with the amount of fibrous matrix. As we have clinical follow-up for these patients, we can identify whether an increase in the amount of CTGF and matrix is associated with poorer patient survival. As matrix appears to be very important, in Aim 3, we will use EHE patient and mouse tumors and employ a methodology called ECM proteomics to identify the proteins that reside in the matrix. Using a technique called scRNA-Seq, we will identify the cellular composition of the tumor and identify the matrix proteins that are secreted by these cells. We will manipulate the levels of key matrix proteins identified through ECM proteomics and scRNA-Seq and probe whether they are needed for tumor growth and spread. RCRP focus areas: We will model EHE to identify disease-defining components of the matrix. Thus, our proposal aligns with “Research Model” and “Biology and Etiology.” Applicability and timelines: This project will (1) produce cell lines and mouse models that can be used to model human EHE, (2) determine how CTGF affects the biology of tumor to promote tumor growth and survival, and (3) pave the way for identifying tumorigenic ECM components that can be targ
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110879
Entities
People
- Brian Rubin
Organizations
- Cleveland Clinic
- United States Army