Preclinical models for the study of pediatric solid tumors: focus on bone sarcomas.

Sarcomas comprise between 10-15% of all pediatric malignancies. Osteosarcoma and Ewing sarcoma are the two most common pediatric bone tumors diagnosed in children and young adults. These tumors are commonly treated with surgery and/or radiation therapy and combination chemotherapy.

Intrinsic Epigenetic State of Primary Osteosarcoma Drives Metastasis.

Osteosarcoma is the most common primary malignant bone tumor affecting the pediatric population with a high potential to metastasize. However, insights into the molecular features enabling its metastatic potential are limited. We mapped the active chromatin landscapes of osteosarcoma tumors by integrating histone H3 lysine-acetylated chromatin state (n = 13), chromatin accessibility profiles (n = 11), and gene expression (n = 13) to understand the differences in their active chromatin profiles and their impact on molecular mechanisms driving the malignant phenotypes.

Identification of an early survival prognostic gene signature for localized osteosarcoma patients.

Osteosarcoma is the most prevalent bone tumor in pediatric patients. Neoadjuvant chemotherapy has improved osteosarcoma patient survival, however the 5-year survival rate for localized osteosarcoma is 75% with a 30-50% recurrence rate. We, therefore, sought to identify a prognostic gene signature which could predict poor prognosis in localized osteosarcoma patients.

Intrinsic epigenetic state of primary osteosarcoma drives metastasis.

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize to distal sites, most commonly the lung. Insights into defining molecular features contributing to metastatic potential are lacking. We have mapped the active chromatin landscapes of OS tumors by integrating histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes.

Decoding the Impact of Tumor Microenvironment in Osteosarcoma Progression and Metastasis.

Osteosarcoma (OS) is a heterogeneous, highly metastatic bone malignancy in children and adolescents. Despite advancements in multimodal treatment strategies, the prognosis for patients with metastatic or recurrent disease has not improved significantly in the last four decades. OS is a highly heterogeneous tumor; its genetic background and the mechanism of oncogenesis are not well defined.

Deciphering the Signaling Mechanisms of Osteosarcoma Tumorigenesis.

Osteosarcoma (OS) is the predominant primary bone tumor in the pediatric and adolescent populations. It has high metastatic potential, with the lungs being the most common site of metastasis. In contrast to many other sarcomas, OS lacks conserved translocations or genetic mutations; instead, it has heterogeneous abnormalities, including somatic DNA copy number alteration, ploidy, chromosomal amplification, and chromosomal loss and gain.

MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM).

Toward quantification of hypoxia using fluorinated Eu-containing ratiometric probes.

Hypoxia is a prognostic biomarker of rapidly growing cancers, where the extent of hypoxia is an indication of tumor progression and prognosis; therefore, hypoxia is also used for staging while performing chemo- and radiotherapeutics for cancer. Contrast-enhanced MRI using Eu-based contrast agents is a noninvasive method that can be used to map hypoxic tumors, but quantification of hypoxia using these agents is challenging due to the dependence of signal on the concentration of both oxygen and Eu. Here, we report a ratiometric method to eliminate concentration dependence of contrast enhancement of hypoxia using fluorinated Eu-containing probes.

Modeling Ewing Sarcoma Lung Metastasis.

Ewing Sarcoma (EwS) is the second most common malignant bone tumor in adolescents and young adults. The single-most powerful predictor of outcome in EwS is presence of metastatic burden at the time of diagnosis. Patients with metastatic Ewing Sarcoma have an abysmal 5-year survival rate of 10%-25%, which has not changed over the past 30-40 years.

Osteogenesis in the presence of chemotherapy: A biomimetic approach.

Osteosarcoma (OS) is the most common bone tumor in pediatrics. After resection, allografts or metal endoprostheses reconstruct bone voids, and systemic chemotherapy is used to prevent recurrence. This urges the development of novel treatment options for the regeneration of bone after excision.

LncRNA PVT-1 promotes osteosarcoma cancer stem-like properties through direct interaction with TRIM28 and TSC2 ubiquitination.

Osteosarcoma, the most common pediatric bone tumor, is an aggressive heterogeneous malignancy defined by complex chromosomal aberrations. Overall survival rates remain at ~70%, but patients with chemoresistant or metastatic disease have extremely poor outcomes of <30%. A subgroup of tumors harbor amplification of chromosome 8q24.

An international working group consensus report for the prioritization of molecular biomarkers for Ewing sarcoma.

The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60-80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects.

A Mouse Holder for Awake Functional Imaging in Unanesthetized Mice: Applications in P Spectroscopy, Manganese-Enhanced Magnetic Resonance Imaging Studies, and Resting-State Functional Magnetic Resonance Imaging.

Anesthesia is often used in preclinical imaging studies that incorporate mouse or rat models. However, multiple reports indicate that anesthesia has significant physiological impacts. Thus, there has been great interest in performing imaging studies in awake, unanesthetized animals to obtain accurate results without the confounding physiological effects of anesthesia.

Dual-Mode Tumor Imaging Using Probes That Are Responsive to Hypoxia-Induced Pathological Conditions.

Hypoxia in solid tumors is associated with poor prognosis, increased aggressiveness, and strong resistance to therapeutics, making accurate monitoring of hypoxia important. Several imaging modalities have been used to study hypoxia, but each modality has inherent limitations. The use of a second modality can compensate for the limitations and validate the results of any single imaging modality.

cBAF complex components and MYC cooperate early in CD8 T cell fate.

The identification of mechanisms to promote memory T (T) cells has important implications for vaccination and anti-cancer immunotherapy. Using a CRISPR-based screen for negative regulators of T cell generation in vivo, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF). Several components of the cBAF complex are essential for the differentiation of activated CD8 T cells into T effector (T) cells, and their loss promotes T cell formation in vivo.

Hereditary retinoblastoma iPSC model reveals aberrant spliceosome function driving bone malignancies.

The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers.

K-Ras and p53 mouse model with molecular characteristics of human rhabdomyosarcoma and translational applications.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, with overall long-term survival rates of ∼65-70%. Thus, additional molecular insights and representative models are critical for identifying and evaluating new treatment modalities. Using MyoD-Cre-mediated introduction of mutant K-RasG12D and perturbations in p53, we developed a novel genetically engineered mouse model (GEMM) for RMS.

Upregulation of miR181a/miR212 Improves Myogenic Commitment in Murine Fusion-Negative Rhabdomyosarcoma.

Fusion-negative rhabdomyosarcoma (FN-RMS) is the most common soft tissue sarcoma of childhood arising from undifferentiated skeletal muscle cells from uncertain origin. Currently used therapies are poorly tumor-specific and fail to tackle the molecular machinery underlying the tumorigenicity and uncontrolled proliferation of FN-RMS. We and other groups recently found that microRNAs (miRNA) network contributes to myogenic epigenetic memory and can influence pluripotent stem cell commitments.

Overcoming PD-1 Inhibitor Resistance with a Monoclonal Antibody to Secreted Frizzled-Related Protein 2 in Metastatic Osteosarcoma.

Secreted frizzled-related protein 2 (SFRP2) promotes the migration/invasion of metastatic osteosarcoma (OS) cells and tube formation by endothelial cells. However, its function on T-cells is unknown. We hypothesized that blocking SFRP2 with a humanized monoclonal antibody (hSFRP2 mAb) can restore immunity by reducing CD38 and PD-1 levels, ultimately overcoming resistance to PD-1 inhibitors.

Research models and mesenchymal/epithelial plasticity of osteosarcoma.

Most osteosarcomas (OSs) develop from mesenchymal cells at the bone with abnormal growth in young patients. OS has an annual incidence of 3.4 per million people and a 60-70% 5-year surviving rate.

Engineering Oncolytic Vaccinia Virus to redirect Macrophages to Tumor Cells.

Oncolytic virotherapy has been tested in numerous early phase clinical studies. However, the antitumor activity of oncolytic viruses thus far has been limited. Numerous strategies are being explored to enhance their antitumor activity by activating the adaptive arm of the immune system.

Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8+ T cells.

Adoptive T cell therapies (ACTs) hold great promise in cancer treatment, but low overall response rates in patients with solid tumors underscore remaining challenges in realizing the potential of this cellular immunotherapy approach. Promoting CD8+ T cell adaptation to tissue residency represents an underutilized but promising strategy to improve tumor-infiltrating lymphocyte (TIL) function. Here, we report that deletion of the HIF negative regulator von Hippel-Lindau (VHL) in CD8+ T cells induced HIF-1α/HIF-2α-dependent differentiation of tissue-resident memory-like (Trm-like) TILs in mouse models of malignancy.

Magnetic resonance thermometry using a Gd-based contrast agent.

The complexes described here serve as contrast agents for magnetic resonance imaging thermometry. The complexes differentially enhance contrast between 275 and 325 K. The basis of the temperature response of the fluorinated contrast complex is the modulation of water exchange caused by trifluoromethyl groups that can be chemically controlled.