Modeling Alveolar Soft Part Sarcoma Unveils Novel Mechanisms of Metastasis

[D.ap]

Abstract

Alveolar soft part sarcoma (ASPS) is a slowly growing, but highly metastatic, sarcoma that affects adolescents and young adults. Its characteristic alveolar structure is constituted by tumor cell nests and an abundant vascular network that is responsible for metastatic activities at the initial stage. Here, we have generated a new ex vivo mouse model for ASPS that well recapitulates associated angiogenic and metastatic phenotypes. In mouse ASPS, the tumor cells frequently showed tumor intravasation, with the intravascular tumor cells presenting as organoid structures covered with hemangiopericytes, which is also observed in human ASPS. High expression of glycoprotein nmb (GPNMB), a transcriptional target of ASPSCR1-TFE3, was observed at the sites of intravasation. ASPS tumor cells also demonstrated enhanced transendothelial migration activity, which was inhibited by silencing of Gpnmb, indicating that GPNMB plays an important role in tumor intravasation, a key step in cancer metastasis. The present model also enabled the evaluation of TFE/MITF family transcription factor function, which demonstrated that ASPSCR1-TFEB possessed definitive albeit less marked oncogenic activity than that of ASPSCR1-TFE3. Collectively, our mouse model provides a tool to understand oncogenic, angiogenic, and metastatic mechanisms of ASPS. It also identifies important motifs within the ASPSCR1-TFE3 fusion protein and provides a platform for developing novel therapeutic strategies for this disorder. Cancer

http://cancerres.aacrjournals.org/content/77/4/897.long

[D.ap]

Introduction

Alveolar soft part sarcoma (ASPS) is a soft-tissue sarcoma affecting adolescents and young adults between 15 and 35 years of age, which is characterized by frequent hematogenous metastases even prior to primary hospital admission (1). The most frequent location of the primary ASPS consists of the deep muscles of the lower extremities; however, the cell of origin remains unidentified (2). Although ASPS represents a slowly growing sarcoma, its prognosis is unfavorable with a survival rate of 60% at 5 years (2, 3). The ASPSCR1-TFE3 fusion gene generated by chromosomal translocation t(X;17)(p11.2;q25) is causally associated with ASPS with the resultant protein modulating its target genes as an oncogenic transcription factor via a DNA-binding motif derived from TFE3 (4–7).

[D.ap]

ASPS has a characteristic alveolar structures of tumor cells separated by thin fibrous septa and a delicate but highly integrative vascular network (2). The abundance of blood vessels causes frequent intravasation of tumor cells, correlated with the high metastatic potential. An upregulation of a series of angiogenesis-related genes has been reported in ASPS (8); however, the mechanisms of modulation in gene expression mediated by ASPSCR1-TFE3 as well as of key target molecules in ASPS vasculogenesis remains to be addressed. Toward this end, the establishment of a reliable animal model that is useful in understanding the tumorigenic and vasculogenic mechanisms of human ASPS is desired.

It has recently been reported that conditional ASPSCR1-TFE3 expression in the mouse resulted in ASPS-like sarcoma (9). In the model, ASPS mainly occurred as intracranial tumors, although, unlike human ASPS, metastatic features were not exhibited. In contrast, in the current study, we present a novel mouse model for ASPS generated using an ex vivo–based technology previously utilized in generation of an Ewing sarcoma model (10). The present model well recapitulates the pathologic and biological features of human ASPS and provides important information toward understanding the mechanisms of vasculogenesis and metastasis.

[Olga]

It is interesting that even in a such a small population disease such a good quality research is done, we are so grateful that there are scientists out there that care about out case...Clinical trials targeting GPNMB with glembatumumab vedotin (Glycoprotein NMB Antibody-Drug Conjugate) are underway in other diseases and additionally high expression of this glycoprotein is found in osteosarcomas and some sub-type of the breast cancer.

[D.ap]

Hello Olga,

I so agree with your voicing of appreciation of these scientist taking their time to study ASPS. I feel that as well.

I think too it’s important to note that like in lung cancer , ASPS has the propensity to go to the brain. Glycoprotein serum levels are tested in lung cancer so I would hope it’s data findings might aid in the present and future /further understanding of treatments for ASPS patients .