Osteosarcoma, the most common bone malignancy of childhood, has been a challenge to treat and cure. Standard chemotherapy regimens work well for many patients, but there remain minimal options for patients with progressive or resistant disease, as clinical trials over recent decades have failed to significantly improve survival. A better understanding of therapy resistance is necessary to improve current treatments and design new strategies for future treatment options. In this review, we discuss known mechanisms and recent scientific advancements regarding osteosarcoma and its patterns of resistance against chemotherapy, radiation, and other newly-introduced therapeutics.

Ewing Sarcoma (ES) is a highly aggressive bone tumor with peak incidence in the adolescent population. It has a high propensity to metastasize, which is associated with dismal survival rates of approximately 25%. To further understand mechanisms of metastasis we investigated microRNA regulatory networks in ES. Our studies focused on miR-130b due to our analysis that enhanced expression of this microRNA has clinical relevance in multiple sarcomas, including ES. Our studies provide insights into a novel positive feedback network involving the direct regulation of miR-130b and activation of downstream signaling events contributing towards sarcoma metastasis. Specifically, we demonstrated miR-130b induces proliferation, invasion, and migration in vitro and increased metastatic potential in vivo. Using microarray analysis of ES cells with differential miR-130b expression we identified alterations in downstream signaling cascades including activation of the CDC42 pathway. We identified Arhgap1, which is a negative regulator of CDC42, as a novel, direct target of miR-130b. In turn, downstream activation of PAK1 activated the JNK and AP-1 cascades and downstream transcriptional targets including IL-8, MMP1 and CCND1. Furthermore, chromatin immunoprecipitation of endogenous AP-1 in ES cells demonstrated direct binding to an upstream consensus binding site within the miR-130b promoter. Finally, small molecule inhibition of PAK1 blocked miR-130b activation of JNK and downstream AP-1 target genes, including primary miR-130b transcripts, and mir-130b oncogenic properties, thus identifying PAK1 as a novel therapeutic target for ES. Taken together, our findings identify and characterize a novel, targetable miR-130b regulatory network that promotes ES metastasis.

Significance Rare human hereditary disorders provide unequivocal evidence of the role of gene mutations in human disease pathogenesis and offer powerful insights into their influence on human disease development. Using a hereditary retinoblastoma (RB) patient–derived induced pluripotent stem cell (iPSC) platform, we elucidate the role of pRB/E2F3a in regulating spliceosomal gene expression. Pharmacological inhibition of the spliceosome in RB1 -mutant cells preferentially increases splicing abnormalities of genes involved in cancer-promoting signaling and impairs cell proliferation and tumorigenesis. Expression of pRB/E2F3a–regulated spliceosomal proteins is negatively associated with pRB expression and correlates with poor clinical outcomes of osteosarcoma (OS) patients. Our findings strongly indicate that the spliceosome is an “Achilles’ heel” of RB1 -mutant OS.