The EHE community, which includes cancer patients and their families from around the world, benefits from the world-class innovative research that takes place at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City (US). In 2019, MSKCC received a $1 million private donation to establish an International Center of Expertise in EHE and since that time, significant knowledge of the disease has been gained and research questions continue to be explored.
To expand upon research initiated as part of the EHE Center of Expertise, The EHE Foundation together with the EHE Rare Cancer Foundation Australia (EHE-RCFA) provided a research grant in 2021 to Cristina Antonescu, MD and Fabio Vanoli, PhD to further investigate the early molecular mechanisms of WWTR1::CAMTA1 and YAP1::TFE3 gene fusions in driving the pathogenesis (the origination and development) of EHE. The research under this specific grant has concluded and Dr. Vanoli recently provided a summary of their research to date:
“Epithelioid hemangioendothelioma (EHE) is a malignant tumor originating from the inner layer of cells covering blood vessels. It affects all ages, but has a distinctive prevalence in young adults. EHE has a ubiquitous presentation, with common sites including liver, lung, and soft tissue. Most tumors have an indolent growth and do not cause symptoms; however, a subset is aggressive, especially in the multifocal setting or pleural involvement. Besides surgical procedures for localized, unifocal lesions, there are no effective therapies, either cytotoxic or targeted, available for EHE patients.
Like many other sarcomas affecting young adults, EHE is characterized at the molecular level by a consistent structural aberration, namely a chromosomal translocation. A translocation occurs when two genes, located on different chromosomes, are fused together creating a new gene able to induce cancer formation. In EHE the two genes that are commonly fused together are WWTR1 and CAMTA1. How the two genes, once fused together, cause the initiation and development of the tumor remains unknown, in part because of the lack of faithful EHE models (e.g., cancer-derived cell line) that allow us to further our understanding of EHE pathogenesis.
The aim of our work at MSKCC is to generate these models and study the mechanism underlying cellular transformation and tumor development. Our approach uses the latest CRISPR-Cas9 modern techniques of genome editing in a human naïve wild type cell line (lacking any other genetic aberrations) to generate a new cell line containing the translocation that fuses together the WWTR1 and CAMTA1 genes. Our methodology, which we successfully developed for the first time in 2017 to model another sarcoma relevant translocation, presents several advantages compared to the more classic strategies. The most relevant is the possibility to induce the expression of the translocation product in a timely regulated matter allowing the study of the early steps of tumorigenesis.
Another important aspect we are addressing is the choice of the appropriate cell type in which the translocation is generated. It is now well known that the same translocation can generate different tumor types depending on the tissue/cell that has been targeted. We are currently investigating the effect of the translocation in endothelial progenitors, the presumed cell of origin of EHE, and we will expand our analysis to more differentiated blood vessel cells. It is pivotal to use the appropriate cell type not only to characterize the mechanism leading to tumorigenesis, but also to evaluate the response to potential therapeutic approaches.
The final goal of our work is to utilize these cell lines as pre-clinical models for drug screening and identification of not yet available targeted therapies to benefit patients with EHE.”
Cristina Antonescu, MD is a co-Investigator of this research and is the Attending Pathologist, Director Bone and Soft Tissue Pathology, Co-Director of Sarcoma Center, Department of Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC) New York, NY.
Fabio Vanoli, PhD is a co-Investigator of this research and is an Assistant Lab Member in the Department of Pathology, Memorial Sloan-Kettering Cancer Center (MSKCC) New York, NY.
The EHE Foundation and EHE-RCFA are grateful to Drs. Vanoli and Antonescu and we look forward to continued advancements in EHE research from their lab.