Osteosarcoma: Molecular Pathogenesis and iPSC Modeling

Osteosarcoma can be derived from undifferentiated/dedifferentiated mesenchymal stem cells and osteoblast-committed cells with differentiation defects. Other than mutations, genomic rearrangements are also involved in osteosarcomagenesis, which may be ignored by traditional mutation analysis. Osteosarcoma-specific fusion genes offer potential therapeutic targets for further osteosarcoma treatment. Insights gained from osteosarcoma-prone diseases highlight numerous interesting concepts linked to cancer development, including differentiation control, tumor-associated immunosuppression, and autophagy. Several osteosarcoma-prone iPSC disease models have been established, including Li–Fraumeni syndrome, hereditary retinoblastoma, Werner syndrome, and Diamond–Blackfan anemia. These systems provide a new platform for modeling and investigating the pathogenesis of osteosarcoma. Rare hereditary disorders provide unequivocal evidence of the importance of genes in human disease pathogenesis. Familial syndromes that predispose to osteosarcomagenesis are invaluable in understanding the underlying genetics of this malignancy. Recently, patient-derived induced pluripotent stem cells (iPSCs) have been successfully utilized to model Li–Fraumeni syndrome (LFS)-associated bone malignancy, demonstrating that iPSCs can serve as an in vitro disease model to elucidate osteosarcoma etiology. We provide here an overview of osteosarcoma predisposition syndromes and review recently established iPSC disease models for these familial syndromes. Merging molecular information gathered from these models with the current knowledge of osteosarcoma biology will help us to gain a deeper understanding of the pathological mechanisms underlying osteosarcomagenesis and will potentially aid in the development of future patient therapies. Rare hereditary disorders provide unequivocal evidence of the importance of genes in human disease pathogenesis. Familial syndromes that predispose to osteosarcomagenesis are invaluable in understanding the underlying genetics of this malignancy. Recently, patient-derived induced pluripotent stem cells (iPSCs) have been successfully utilized to model Li–Fraumeni syndrome (LFS)-associated bone malignancy, demonstrating that iPSCs can serve as an in vitro disease model to elucidate osteosarcoma etiology. We provide here an overview of osteosarcoma predisposition syndromes and review recently established iPSC disease models for these familial syndromes. Merging molecular information gathered from these models with the current knowledge of osteosarcoma biology will help us to gain a deeper understanding of the pathological mechanisms underlying osteosarcomagenesis and will potentially aid in the development of future patient therapies. a double-layered membranous structure formed during the process of autophagy. By fusing with the lysosome, the cell can clear unnecessary or dysfunctional components. a normal destructive mechanism of the cell to clean up dysfunctional components and recycle usable materials. a process that removes DNA base lesions induced by oxidation, deamination, and alkylation. plural of calvarium, the upper portion of the skull composed of the occipital, frontal, and parietal bones that cover the cranial cavity containing the brain, excluding the jaw and facial regions. extensive chromosomal rearrangements that occur in one or a few chromosomes. This chromosomal patchwork pattern leads to genomic chaos. genome-editing methodology built from guide RNA (gRNA)-conjugated DNA nuclease or nickase. The CRISPR/Cas9 system borrows from the bacterial immune system that defends against foreign genetic elements to produce CRISPR RNA (crRNA) based on foreign RNA material. The CRISPR/Cas9 system comprises a gRNA for recognition, and Cas9 for cleavage. The Cas/crRNA complex can target and cut DNA at an arbitrary site based on base-pairing to complementary RNA. Currently, this system is the most convenient methodology for genome editing, although the more accurate but limited paired CRISPR/Cas9 nickase system is also available to target genomic loci. Cas9 will not successfully bind and cleave target DNA regions unless they contain the 5′NGG3′ protospacer adjacent motif (PAM) sequence. some genes are duplicated or deleted in the genome. A difference in the duplication number of a repeated genome area defines its copy-number alteration. the process that repairs DNA with breaks in both strands. cells isolated from the inner cell mass of the blastocyst at the preimplantation stage and cultured. These cells can differentiate into all adult lineages (pluripotency) or proliferate indefinitely without differentiation (self-renewal), based on the environmental conditions. bony tissue at the end of a long bone. Before bone growth completes, it is separated from the bone shaft by the growth plate cartilage. After that, it is connected to the bone shaft by ossification of growth plate cartilage. the transition of a cancer cell from an epithelial to a mesenchymal morphology, allowing for the movement of the cancer cell into lymph and blood vessels, thereby promoting metastasis. To accomplish this, several genes (e.g., those encoding E-cadherin, SNAIL and TWIST) are alternatively regulated. a genetic disease that causes bone marrow failure to produce new blood cells and increases the risk of some types of cancer. a DNA structure comprising four dsDNA strands that is formed during homologous recombination. Named after Robin Holliday. the exchange of DNA sequences between homologous DNA strands. a specific group of imprinted genes with correlated expression. These genes coregulate each other’s expression during embryonic growth. The IGN may control a complex regulatory network to induce rapid but controlled developmental processes. by introducing defined factors (e.g., the ‘Yamanaka factors’ OCT4, SOX2, KLF4, and MYC), fully differentiated somatic cells can be reprogrammed into PSCs and gain full differentiation abilities. a large number of mutations located at particular genomic positions rather than being spread throughout the genome. Kataegis (Greek for ‘thunderstorm’), represents the nature of clustering of this mutational thunderstorm. Chromosomal rearrangements are also involved in these regions. tumors bearing histological features of leiomyosarcoma during in vivo tumor formation. Leiomyosarcoma is a soft-tissue sarcoma arising from smooth muscle cells. the complexes formed by mitochondrial DNA (mtDNA) and proteins within mitochondria. the pathway to repair ds breaks by direct ligation of two broken DNA strands. It is an error-prone process. a DNA repair mechanism that eliminates DNA lesions induced by UV irradiation. spherical structures found in the nuclear matrix, are generally composed exclusively of proteins. They play important roles in transcription, apoptosis, and the DNA damage response. alterations in the DNA sequence comprising only a single-nucleotide change. the breaking and rejoining of DNA sequences between two sister chromatids of one chromosome during DNA replication. variation in a DNA region >1 kb in length arising from insertions, deletions, duplications, copy-number alterations, inversions, or translocations that change the structure of the affected region. highly accurate genome-editing methodology that combines the FokI restriction enzyme with transcription activator-like effectors (TALEs). TALEs are derived from Xanthomonas bacteria and are built from highly conserved 33–34 amino acid sequences, each of which can recognize a unique base pair. Like ZFNs, target recognition brings FokI to a specific location and permits induction of a ds break. a cytogenetic characteristic of Werner syndrome (WS) fibroblasts in which chromosomal rearrangements in cell lines isolated from an individual patient demonstrate a clonal effect. the process of analyzing the complete DNA sequence of an organism. It provides comprehensive genetic information and can be used to identify all variations from a reference genome. this genome-editing methodology employs FokI restriction enzyme-conjugated zinc-finger proteins. Two zinc-finger proteins, each targeted to a specific strand of DNA in opposite directions, work together to define the targeting site. The FokI restriction enzyme domains, brought together by the zinc-finger domains, function only as a dimer, allowing sequence and orientation specificity to generate a ds break and facilitate homologous recombination.