Defining the Extracellular Matrix of Rhabdomyosarcoma

Abstract

Background: 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.Methods: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 4 human sarcomas to analyze expression of 7 different collagens, fibrillins and collagen-modifying proteins, with cross-correlation to RNA deep sequencing.Results: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.Conclusion: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.

DWI and IVIM Imaging in a Murine Model of Rhabdomyosarcoma: Correlations with Quantitative Histopathologic Features

“…Most previous studies focused on events that happened within tumor cells, several recent studies addressed the role of the microenvironment in tumor tissue components when stimulating tumor progression, invasion, and metastasis 29,30 . The mechanism of tumor–stroma interaction is of therapeutic importance.…”

“…Most previous studies focused on events that happened within tumor cells, several recent studies addressed the role of the microenvironment in tumor tissue components when stimulating tumor progression, invasion, and metastasis. 29,30 The mechanism of tumor-stroma interaction is of therapeutic importance. Patients with collagen-rich stroma tumors are typically at higher risk of metastasis and this combination creates barriers to systemic radiotherapy and chemotherapy by promoting tumor invasion.…”

Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

“…Given previous studies suggesting the importance of the extracellular matrix (ECM) in sarcoma, 17 we investigated the expression patterns of extracellular matrix genes in EPS (Figure S6). Four ECM genes were significantly overexpressed in distal EPS ( COL4A1 , 3.3× overexpression, COL5A , 4.2× overexpression, COL12A1 , 2.5× overexpression, COLEC12 , 1.5× overexpression), but significance did not hold true under multiple comparison testing.…”

Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma

“…For instance, collagens play important roles in metastasis through regulation of the tumour microenvironment. COL18A1 is known to be upregulated in RMS and linked to poorer survival [64]. COL1A1 expression is linked to metastasis and poor survival in breast cancer [65], colorectal cancer [66], hepatocellular carcinoma [67], lung cancer [68], and ovarian cancer [69].…”