Interactions in CSF1-Driven Tenosynovial Giant Cell Tumors

Abstract

Purpose: A major component of cells in Tenosynovial Giant Cell Tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here we use single cell RNA sequencing to investigate cellular interactions in TGCT. Experimental Design: A total of 18,788 single cells from three TGCT and two Giant Cell Tumor of Bone (GCTB) samples underwent singe cell RNAseq. The three TGCTs were additionally analyzed using long read RNA sequencing. Immunofluorescence and immunohistochemistry for a range of markers was used to validate and extend the scRNAseq findings. Results: Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to non-neoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping features between the giant cells in TGCT and GCTB. Conclusions/Discussion: The neoplastic cells in TGCT are highly similar non-neoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the PDGF receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

A novel colony‐stimulating factor 1 (CSF1) translocation involving human endogenous retroviral element in a tenosynovial giant cell tumor

“…There is increasing evidence that shows the regulatory element or membrane domain loss by losing various proportions of the 3′ end of CSF1 and new research indicates that the self‐sustaining autocrine CSF1‐CSF1R signaling loop in neoplastic cells is lacking based on single‐cell sequencing. 8 …”

“… 6 The clonal population expresses high levels of colony‐stimulating factor 1 (CSF1), which leads to the recruitment of non‐neoplastic cells expressing the CSF1 receptor (CSF1R). This is referred to as the “landscape effect.” 6 , 7 , 8 …”

Exploration of the molecular biological mechanisms and review of postoperative radiotherapy cases in tenosynovial giant cell tumors

“…Tendon sheath giant cell tumor (TGCT) is a benign tumor that primarily grows within joints and bursae, or extends along the tendon sheath ( 1 ). This type of tumor originates from synovial cells or mesenchymal cells differentiated into synovial cells ( 1 ). TGCT can be classified into two types: localized and diffuse ( 2 ).…”

Identification of potential diagnostic biomarkers for tenosynovial giant cell tumour by integrating microarray and single-cell RNA sequencing data

“…Several studies have combined them to construct a prognosis model [ 10 ] and show the landscape of the immune microenvironment [ 11 ] and the mechanisms of biological processes [ 12 ]. Using sequencing techniques, researchers revealed that osteoclastogenesis and osteoclast differentiation are vital characteristics of TGCT [ 13 , 14 ]. However, no studies explore the possibility of diagnosing TGCT using osteoclast-specific genes.…”

“…In this study, we integrated two scRNA-seq datasets [ 14 , 15 ] and two microarray datasets [ 13 , 16 ] from Gene Expression Omnibus (GEO) dataset to identify osteoclast-specific up-regulated genes (OCSURGs) to predict the diagnosis of TGCT. Up-regulated genes were screened from the discovering cohort (GSE3698, GSE210750, and GSE152805).…”