Abstract
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood with a propensity to metastasize. Current treatment for patients with RMS includes conventional systemic chemotherapy, radiation therapy, and surgical resection; nevertheless, little to no improvement in long term survival has been achieved in decades—underlining the need for target discovery and new therapeutic approaches to targeting tumor cells or the tumor microenvironment. To evaluate cross-species sarcoma extracellular matrix production, we have used murine models which feature knowledge of the myogenic cell-of-origin. With focus on the RMS/undifferentiated pleomorphic sarcoma (UPS) continuum, we have constructed tissue microarrays of 48 murine and four human sarcomas to analyze expression of seven different collagens, fibrillins, and collagen-modifying proteins, with cross-correlation to RNA deep sequencing. We have uncovered that RMS produces increased expression of type XVIII collagen alpha 1 (COL18A1), which is clinically associated with decreased long-term survival. We have also identified significantly increased RNA expression of COL4A1, FBN2, PLOD1, and PLOD2 in human RMS relative to normal skeletal muscle. These results complement recent studies investigating whether soft tissue sarcomas utilize collagens, fibrillins, and collagen-modifying enzymes to alter the structural integrity of surrounding host extracellular matrix/collagen quaternary structure resulting in improved ability to improve the ability to invade regionally and metastasize, for which therapeutic targeting is possible.
Highlights
Rhabdomyosarcoma (RMS) are highly malignant tumors known to phenocopy some of the early events in skeletal muscle embryogenesis but are known to arise from tissues not known to contain striated muscle or muscle stem cells [1]
Fibrillin-1 (FBN1) and fibrillin-2 (FBN2) are two subtypes of the fibrillin glycoprotein incorporated into elastic tissue in the extracellular matrix, and FBN2 is a known immunohistochemical biomarker of Embryonal rhabdomyosarcoma (eRMS) [26], which was reflected at the RNA level for eRMS more so than alveolar rhabdomyosarcoma (aRMS)
As individual prognostic markers, increased COL18A1, COL4A1, and COL4A2 expressions are all associated with decreased long-term survival in all pediatric RMS subtypes, with the alveolar subtype showing worsened survival versus other subtypes. aRMS is most often fatal when metastatic [29], yet recent studies of related soft tissue sarcomas suggest that collagen subtype and modification can determine the ease with which these sarcomas metastasize [14]; altering collagen modifications is therapeutically amenable with FDA-approved agents that suppress metastasis in mouse soft tissue sarcoma models
Summary
Rhabdomyosarcoma (RMS) are highly malignant tumors known to phenocopy some of the early events in skeletal muscle embryogenesis but are known to arise from tissues not known to contain striated muscle or muscle stem cells [1]. Lymphatic and hematogenous (pulmonary) metastasis is a predominant feature [4] and a primary cause of mortality in these models [9] We characterized these soft tissue sarcoma models and demonstrate them to be representative of the human diseases by histopathology, gene expression and other features [3, 4, 8, 10]. These conditional models have the special features of knowing the cell-of-origin as well as the mutational profile making them a valuable tool to study RMS (Figure 1)
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