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1.
Nature ; 607(7917): 135-141, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35732731

RESUMEN

The identification of mechanisms to promote memory T (Tmem) cells has important implications for vaccination and anti-cancer immunotherapy1-4. Using a CRISPR-based screen for negative regulators of Tmem cell generation in vivo5, here we identify multiple components of the mammalian canonical BRG1/BRM-associated factor (cBAF)6,7. Several components of the cBAF complex are essential for the differentiation of activated CD8+ T cells into T effector (Teff) cells, and their loss promotes Tmem cell formation in vivo. During the first division of activated CD8+ T cells, cBAF and MYC8 frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high MYC and high cBAF display a cell fate trajectory towards Teff cells, whereas those with low MYC and low cBAF preferentially differentiate towards Tmem cells. The cBAF complex and MYC physically interact to establish the chromatin landscape in activated CD8+ T cells. Treatment of naive CD8+ T cells with a putative cBAF inhibitor during the first 48 h of activation, before the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves efficacy in a mouse solid tumour model. Our results establish cBAF as a negative determinant of Tmem cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve cancer immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Diferenciación Celular , ADN Helicasas , Complejos Multiproteicos , Proteínas Nucleares , Proteínas Proto-Oncogénicas c-myc , Factores de Transcripción , Animales , Linfocitos T CD8-positivos/citología , ADN Helicasas/metabolismo , Modelos Animales de Enfermedad , Memoria Inmunológica , Inmunoterapia , Células T de Memoria/citología , Ratones , Complejos Multiproteicos/química , Complejos Multiproteicos/metabolismo , Neoplasias , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Quiméricos de Antígenos , Factores de Transcripción/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(15): e2220891120, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-37018203

RESUMEN

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 EuII-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 EuII. Here, we report a ratiometric method to eliminate concentration dependence of contrast enhancement of hypoxia using fluorinated EuII/III-containing probes. We studied three different EuII/III couples of complexes containing 4, 12, or 24 fluorine atoms to balance fluorine signal-to-noise ratio with aqueous solubility. The ratio between the longitudinal relaxation time (T1) and 19F signal of solutions containing different ratios of EuII- and EuIII-containing complexes was plotted against the percentage of EuII-containing complexes in solution. We denote the slope of the resulting curves as hypoxia indices because they can be used to quantify signal enhancement from Eu, that is related to oxygen concentration, without knowledge of the absolute concentration of Eu. This mapping of hypoxia was demonstrated in vivo in an orthotopic syngeneic tumor model. Our studies significantly contribute toward improving the ability to radiographically map and quantify hypoxia in real time, which is critical to the study of cancer and a wide range of diseases.


Asunto(s)
Flúor , Neoplasias , Humanos , Imagen por Resonancia Magnética/métodos , Hipoxia , Oxígeno
3.
Proc Natl Acad Sci U S A ; 119(16): e2117857119, 2022 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-35412907

RESUMEN

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 iPSC­derived 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. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a­regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.


Asunto(s)
Neoplasias Óseas , Carcinogénesis , Factor de Transcripción E2F3 , Regulación Neoplásica de la Expresión Génica , Células Madre Pluripotentes Inducidas , Osteosarcoma , Proteínas de Unión a Retinoblastoma , Empalmosomas , Ubiquitina-Proteína Ligasas , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Carcinogénesis/genética , Factor de Transcripción E2F3/genética , Factor de Transcripción E2F3/metabolismo , Genes de Retinoblastoma , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación , Osteosarcoma/genética , Osteosarcoma/patología , Neoplasias de la Retina/genética , Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Empalmosomas/genética , Empalmosomas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
4.
Int J Mol Sci ; 24(14)2023 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-37511127

RESUMEN

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. Unfortunately, clinical outcomes have not significantly improved in over 30 years. Currently, no effective molecularly targeted therapies are available for this disease. Several genomic studies showed inactivation in the tumor suppressor genes, including p53, RB, and ATRX, and hyperactivation of the tumor promoter genes, including MYC and MDM2, in OS. Alterations in the major signaling pathways, including the PI3K/AKT/mTOR, JAK/STAT, Wnt/ß-catenin, NOTCH, Hedgehog/Gli, TGF-ß, RTKs, RANK/RANKL, and NF-κB signaling pathways, have been identified in OS development and metastasis. Although OS treatment is currently based on surgical excision and systematic multiagent therapies, several potential targeted therapies are in development. This review focuses on the major signaling pathways of OS, and we propose a biological rationale to consider novel and targeted therapies in the future.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Adolescente , Humanos , Niño , Fosfatidilinositol 3-Quinasas , Proteínas Hedgehog , Osteosarcoma/metabolismo , Carcinogénesis/genética , Transformación Celular Neoplásica , Neoplasias Óseas/metabolismo
5.
Ann Surg Oncol ; 26(13): 4782-4790, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31515721

RESUMEN

BACKGROUND: We previously reported that secreted frizzled-related protein-2 (SFRP2) is expressed in a variety of tumors, including sarcoma and breast carcinoma, and stimulates angiogenesis and inhibits tumor apoptosis. Therefore, we hypothesized that a humanized SFRP2 monoclonal antibody (hSFRP2 mAb) would inhibit tumor growth. METHODS: The lead hSFRP2 antibody was tested against a cohort of 22 healthy donors using a time course T-cell assay to determine the relative risk of immunogenicity. To determine hSFRP2 mAb efficacy, nude mice were subcutaneously injected with SVR angiosarcoma cells and treated with hSFRP2 mAb 4 mg/kg intravenously every 3 days for 3 weeks. We then injected Hs578T triple-negative breast cells into the mammary fat pad of nude mice and treated for 40 days. Control mice received an immunoglobulin (Ig) G1 control. The SVR and Hs578T tumors were then stained using a TUNEL assay to detect apoptosis. RESULTS: Immunogenicity testing of hSFRP2 mAb did not induce proliferative responses using a simulation index (SI) ≥ 2.0 (p < 0.05) threshold in any of the healthy donors. SVR angiosarcoma tumor growth was inhibited in vivo, evidenced by significant tumor volume reduction in the hSFRP2 mAb-treated group, compared with controls (n = 10, p < 0.001). Likewise, Hs578T triple-negative breast tumors were smaller in the hSFRP2 mAb-treated group compared with controls (n = 10, p < 0.001). The hSFRP2 mAb treatment correlated with an increase in tumor cell apoptosis (n = 11, p < 0.05). Importantly, hSFRP2 mAb treatment was not associated with any weight loss or lethargy. CONCLUSION: We present a novel hSFRP2 mAb with therapeutic potential in breast cancer and sarcoma that has no effect on immunogenicity.


Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Apoptosis , Hemangiosarcoma/tratamiento farmacológico , Proteínas de la Membrana/inmunología , Neovascularización Patológica/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales Humanizados/biosíntesis , Proliferación Celular , Femenino , Hemangiosarcoma/metabolismo , Hemangiosarcoma/patología , Humanos , Ratones , Ratones Desnudos , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Pediatr Blood Cancer ; 66(4): e27579, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30548185

RESUMEN

One of the limitations of performing percutaneous biopsies in patients with bone sarcomas is the small amount of tumor that can be obtained for research purposes. Here, we describe our experience developing patient-derived tumor xenografts (PDXs) using percutaneous tumor biopsies in children with bone sarcomas. We generated 14 bone sarcoma PDXs from percutaneous tumor biopsies. We also developed eight bone sarcoma PDXs from surgical resection of primary bone tumors and pulmonary metastases. A multidisciplinary team approach was critical to establish an accurate diagnosis and to provide adequate tumor samples for PDX generation.


Asunto(s)
Neoplasias Óseas , Neoplasias Pulmonares , Osteosarcoma , Adolescente , Adulto , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/terapia , Niño , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/terapia , Masculino , Metástasis de la Neoplasia , Osteosarcoma/metabolismo , Osteosarcoma/patología , Osteosarcoma/terapia , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Int J Cancer ; 141(10): 2062-2075, 2017 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-28748534

RESUMEN

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 toward 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.


Asunto(s)
Neoplasias Óseas/patología , Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , MicroARNs/genética , Sarcoma de Ewing/patología , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Retroalimentación Fisiológica , Proteínas Activadoras de GTPasa/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos NOD , Ratones SCID , Estadificación de Neoplasias , Pronóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Transducción de Señal , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismo
8.
BMC Cancer ; 16(1): 869, 2016 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-27821163

RESUMEN

BACKGROUND: Osteosarcoma (OS), which has a high potential for developing metastatic disease, is the most frequent malignant bone tumor in children and adolescents. Molecular analysis of a metastatic genetically engineered mouse model of osteosarcoma identified enhanced expression of Secreted Frizzled-Related Protein 2 (sFRP2), a putative regulator of Wnt signaling within metastatic tumors. Subsequent analysis correlated increased expression in the human disease, and within highly metastatic OS cells. However, the role of sFRP2 in osteosarcoma development and progression has not been well elucidated. METHODS: Studies using stable gain or loss-of-function alterations of sFRP2 within human and mouse OS cells were performed to assess changes in cell proliferation, migration, and invasive ability in vitro, via both transwell and 3D matrigel assays. In additional, xenograft studies using overexpression of sFRP2 were used to assess effects on in vivo metastatic potential. RESULTS: Functional studies revealed stable overexpression of sFRP2 within localized human and mouse OS cells significantly increased cell migration and invasive ability in vitro and enhanced metastatic potential in vivo. Additional studies exploiting knockdown of sFRP2 within metastatic human and mouse OS cells demonstrated decreased cell migration and invasion ability in vitro, thus corroborating a critical biological phenotype carried out by sFRP2. Interestingly, alterations in sFRP2 expression did not alter OS proliferation rates or primary tumor development. CONCLUSIONS: While future studies further investigating the molecular mechanisms contributing towards this sFRP2-dependent phenotype are needed, our studies clearly provide evidence that aberrant expression of sFRP2 can contribute to the invasive and metastatic potential for osteosarcoma.


Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Proteínas de la Membrana/metabolismo , Osteosarcoma/metabolismo , Osteosarcoma/patología , Animales , Neoplasias Óseas/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Proteínas de la Membrana/genética , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Osteosarcoma/genética
9.
Genes Chromosomes Cancer ; 54(12): 796-808, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26355645

RESUMEN

Osteosarcomas (OSs) are characterized by high levels of genomic instability (GI). To gain insights into the GI and its contribution toward understanding the genetic basis of OS, we characterized 19 primary and 13 metastatic mouse tumors in a genetically engineered novel mouse model of OS by a combination of genomic techniques. Through the bone-specific deletion of the wild-type Trp53 locus or activation of a metastatic-promoting missense R172Hp53 allele, C57BL/6 mice developed either localized or metastatic OS. Subsequent tumors were isolated and primary cultures created from primary bone and/or distal metastatic lesions, for example, lung and liver. These tumors exhibited high levels of GI with complex chromosomal rearrangements, amplifications, and deletions comparable to human OS. The combined genomic approaches identified frequent amplification of chromosome 15D1 and loss of 11B4 by CGH and/or SKY. Both 15D1 and 11B4 have homology with frequently altered chromosomal bands 8q24 and 17p13 in human OS, respectively. Subsequent array CGH, FISH, and qRT-PCR analysis identified coamplification and overexpression of Myc/Pvt1 transcripts from the 15D1 amplicon and loss and decreased expression of the Nlrp1b from 11B4. The Nlrp1 gene is the key mediator of apoptosis and interacts strongly with caspase 2.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/genética , Neoplasias Óseas/genética , Osteosarcoma/genética , Proteínas Proto-Oncogénicas c-myc/genética , ARN Largo no Codificante/genética , Sarcoma Experimental/genética , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis , Proteínas Reguladoras de la Apoptosis/metabolismo , Neoplasias Óseas/patología , Caspasa 2/metabolismo , Deleción Cromosómica , Amplificación de Genes , Sitios Genéticos , Inestabilidad Genómica , Homocigoto , Hibridación Fluorescente in Situ , Cariotipificación , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mutación Missense , Metástasis de la Neoplasia , Análisis de Secuencia por Matrices de Oligonucleótidos , Osteoblastos/metabolismo , Osteosarcoma/patología , Cultivo Primario de Células , Sarcoma Experimental/patología , Regulación hacia Arriba
10.
Br J Cancer ; 113(9): 1289-97, 2015 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-26528706

RESUMEN

BACKGROUND: Osteosarcoma (OS) is the most common bone malignancy in the paediatric population, principally affecting adolescents and young adults. Minimal advancements in patient prognosis have been made over the past two decades because of the poor understanding of disease biology. Runx2, a critical transcription factor in bone development, is frequently amplified and overexpressed in OS. However, the molecular and biological consequences of Runx2 overexpression remain unclear. METHODS: si/shRNA and overexpression technology to alter Runx2 levels in OS cells. In vitro assessment of doxorubicin (doxo)-induced apoptosis and in vivo chemosensitivity studies. Small-molecule inhibitor of c-Myc transcriptional activity was used to assess its role. RESULTS: Loss of Runx2 sensitises cells to doxo-induced apoptosis both in vitro and in vivo. Furthermore, in conjunction with chemotherapy, decreasing Runx2 protein levels activates both the intrinsic and extrinsic apoptotic pathways. Transplanted tumour studies demonstrated that loss of endogenous Runx2 protein expression enhances caspase-3 cleavage and tumour necrosis in response to chemotherapy. Finally, upon doxo-treated Runx2 knockdown OS cells there was evidence of enhanced c-Myc expression and transcriptional activity. Inhibition of c-Myc under these conditions resulted in decreased activation of apoptosis, therefore insinuating a role for c-Myc in dox-induced activation of apoptotic pathways. CONCLUSIONS: Therefore, we have established a novel molecular mechanism by which Runx2 provides a chemoprotective role in OS, indicating that in conjunction to standard chemotherapy, targeting Runx2 may be a new therapeutic strategy for patients with OS.


Asunto(s)
Apoptosis/genética , Neoplasias Óseas/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Osteosarcoma/genética , Animales , Apoptosis/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Caspasa 3/genética , Línea Celular Tumoral , Doxorrubicina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Ratones , Ratones Desnudos , Osteosarcoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/genética , ARN Interferente Pequeño/genética , Activación Transcripcional/efectos de los fármacos , Activación Transcripcional/genética
11.
Bioinformatics ; 29(9): 1182-9, 2013 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-23457041

RESUMEN

MOTIVATION: Although chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) or tiling array hybridization (ChIP-chip) is increasingly used to map genome-wide-binding sites of transcription factors (TFs), it still remains difficult to generate a quality ChIPx (i.e. ChIP-seq or ChIP-chip) dataset because of the tremendous amount of effort required to develop effective antibodies and efficient protocols. Moreover, most laboratories are unable to easily obtain ChIPx data for one or more TF(s) in more than a handful of biological contexts. Thus, standard ChIPx analyses primarily focus on analyzing data from one experiment, and the discoveries are restricted to a specific biological context. RESULTS: We propose to enrich this existing data analysis paradigm by developing a novel approach, ChIP-PED, which superimposes ChIPx data on large amounts of publicly available human and mouse gene expression data containing a diverse collection of cell types, tissues and disease conditions to discover new biological contexts with potential TF regulatory activities. We demonstrate ChIP-PED using a number of examples, including a novel discovery that MYC, a human TF, plays an important functional role in pediatric Ewing sarcoma cell lines. These examples show that ChIP-PED increases the value of ChIPx data by allowing one to expand the scope of possible discoveries made from a ChIPx experiment. AVAILABILITY: http://www.biostat.jhsph.edu/~gewu/ChIPPED/


Asunto(s)
Inmunoprecipitación de Cromatina/métodos , Factores de Transcripción/metabolismo , Transcriptoma , Animales , Sitios de Unión , Línea Celular Tumoral , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Secuencia de ADN
12.
Mol Cancer Res ; 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38842581

RESUMEN

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize. However, insights into the molecular features enabling its metastatic potential are limited. We mapped the active chromatin landscapes of OS 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 its impact on molecular mechanisms driving the malignant phenotypes. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to those without metastasis (localized). This difference shapes the transcriptional profile of OS. We identified novel candidate genes, including PPP1R1B, PREX1 and IGF2BP1, which exhibit increased chromatin activity in primary met. Loss of PREX1 in primary met OS cells significantly diminishes OS proliferation, invasion, migration, and colony formation capacity. Differential chromatin activity in primary met is associated with genes regulating cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Chromatin profiling of tumors from metastatic lung lesions shows increased chromatin activity in genes involved in cell migration and Wnt pathway. This data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors, with cellular chromatin profiles further adapting for successful dissemination, migration, and colonization at the distal site. Implications: Our study demonstrates that metastatic potential is intrinsic to primary metastatic osteosarcoma tumors, with chromatin profiles further adapting for successful dissemination, migration and colonization at distal metastatic site.

13.
ACS Biomater Sci Eng ; 10(3): 1646-1660, 2024 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-38350651

RESUMEN

Osteosarcoma (OS) is the most common primary malignant bone tumor, and the current standard of care for OS includes neoadjuvant chemotherapy, followed by an R0 surgical resection of the primary tumor, and then postsurgical adjuvant chemotherapy. Bone reconstruction following OS resection is particularly challenging due to the size of the bone voids and because patients are treated with adjuvant and neoadjuvant systemic chemotherapy, which theoretically could impact bone formation. We hypothesized that an osteogenic material could be used in order to induce bone regeneration when adjuvant or neoadjuvant chemotherapy is given. We utilized a biomimetic, biodegradable magnesium-doped hydroxyapatite/type I collagen composite material (MHA/Coll) to promote bone regeneration in the presence of systemic chemotherapy in a murine critical size defect model. We found that in the presence of neoadjuvant or adjuvant chemotherapy, MHA/Coll is able to enhance and increase bone formation in a murine critical size defect model (11.16 ± 2.55 or 13.80 ± 3.18 versus 8.70 ± 0.81 mm3) for pre-op cisplatin + MHA/Coll (p-value = 0.1639) and MHA/Coll + post-op cisplatin (p-value = 0.1538), respectively, at 12 weeks. These findings indicate that neoadjuvant and adjuvant chemotherapy will not affect the ability of a biomimetic scaffold to regenerate bone to repair bone voids in OS patients. This preliminary data demonstrates that bone regeneration can occur in the presence of chemotherapy, suggesting that there may not be a necessity to modify the current standard of care concerning neoadjuvant and adjuvant chemotherapy for the treatment of metastatic sites or micrometastases.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Humanos , Animales , Ratones , Cisplatino/farmacología , Cisplatino/uso terapéutico , Modelos Animales de Enfermedad , Osteosarcoma/tratamiento farmacológico , Regeneración Ósea , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía
14.
Sci Rep ; 14(1): 7327, 2024 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-38538763

RESUMEN

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. Using the TARGET osteosarcoma transcriptomic dataset, we identified a 13-hub gene signature associated with overall survival and time to death of localized osteosarcoma patients, with the high-risk group showing a 22% and the low-risk group showing 100% overall survival. Furthermore, network analysis identified five modules of co-expressed genes that significantly correlated with survival, and identified 65 pathways enriched across 3 modules, including Hedgehog signaling, which includes 2 of the 13 genes, IHH and GLI1. Subsequently, we demonstrated that GLI antagonists inhibited growth of a recurrent localized PDX-derived cell line with elevated IHH and GLI1 expression, but not a non-relapsed cell line with low pathway activation. Finally, we show that our signature outperforms previously reported signatures in predicting poor prognosis and death within 3 years in patients with localized osteosarcoma.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Humanos , Niño , Pronóstico , Proteína con Dedos de Zinc GLI1/genética , Proteína con Dedos de Zinc GLI1/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Osteosarcoma/patología , Neoplasias Óseas/metabolismo
15.
Curr Oncol Rep ; 15(4): 296-307, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23690089

RESUMEN

Primary malignant bone tumors in the pediatric to young adult populations are relatively uncommon and account for about 6 % of all cancers in those less than 20 years old [1] and 3 % of all cancers in adolescents and young adults (AYA) within the age range of 15 to 29 years [2]. Osteosarcoma (OS) and Ewing's sarcoma (ES) comprise the majority of malignant bone tumors. The approach to treatment for both tumors consists of local control measures (surgery or radiation) as well as systemic therapy with high-dose chemotherapy. Despite earlier advances, there have been no substantial improvements in outcomes over the past several decades, particularly for patients with metastatic disease. This review summarizes the major advances in the treatment of OS and ES and the standard therapies available today, current active clinical trials, and areas of investigation into molecularly targeted therapies.


Asunto(s)
Neoplasias Óseas/terapia , Adolescente , Adulto , Antineoplásicos/uso terapéutico , Neoplasias Óseas/diagnóstico , Ensayos Clínicos como Asunto , Humanos , Terapia Molecular Dirigida/métodos , Estadificación de Neoplasias , Adulto Joven
16.
Proc Natl Acad Sci U S A ; 107(8): 3534-9, 2010 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-20133585

RESUMEN

Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein-Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the gamma-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.


Asunto(s)
Transformación Celular Neoplásica/genética , Regulación Leucémica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/genética , Linfoma de Células B/genética , Proteínas de la Membrana/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Receptores Notch/metabolismo , Animales , Linfocitos B/metabolismo , Hipoxia de la Célula/genética , Proliferación Celular , Dipéptidos/farmacología , Perfilación de la Expresión Génica , Humanos , Proteína Jagged-2 , Ratones , Modelos Biológicos , Interferencia de ARN , Receptores Notch/antagonistas & inhibidores , Receptores Notch/genética , Activación Transcripcional
17.
bioRxiv ; 2023 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-38014160

RESUMEN

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. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to primary tumors from patients without metastatic disease (localized). The difference in chromatin activity shapes the transcriptional profile of OS. We identified novel candidate genes involved in OS pathogenesis and metastasis, including PPP1R1B, PREX1 and IGF2BP1, which exhibit increased chromatin activity in primary met along with higher transcript levels. Overall, differential chromatin activity in primary met occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Furthermore, chromatin profiling of tumors from metastatic lung lesions noted increases in chromatin activity in genes involved in cell migration and key intracellular signaling cascades, including the Wnt pathway. Thus, this data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors and the cellular chromatin profiles further adapt to allow for successful dissemination, migration, and colonization at the distal metastatic site.

18.
Cancers (Basel) ; 15(20)2023 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-37894474

RESUMEN

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. Unfortunately, no effective molecular targeted therapy is currently available for this disease. Understanding osteosarcoma's tumor microenvironment (TME) has recently gained much interest among scientists hoping to provide valuable insights into tumor heterogeneity, progression, metastasis, and the identification of novel therapeutic avenues. Here, we review the current understanding of the TME of OS, including different cellular and noncellular components, their crosstalk with OS tumor cells, and their involvement in tumor progression and metastasis. We also highlight past/current clinical trials targeting the TME of OS for effective therapies and potential future therapeutic strategies with negligible adverse effects.

19.
JCI Insight ; 8(13)2023 07 10.
Artículo en Inglés | MEDLINE | ID: mdl-37279073

RESUMEN

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). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that hyperactivation of MYC led to an immune-depleted TME in OS demonstrated by the reduced number of leukocytes, particularly macrophages. MYC hyperactivation led to the downregulation of macrophage colony-stimulating factor 1, through increased microRNA 17/20a expression, causing a reduction of macrophage population in the TME of OS. Furthermore, we developed cell lines from the GEMM tumors, including a degradation tag-MYC model system, which validated our MYC-dependent findings both in vitro and in vivo. Our studies utilized innovative and clinically relevant models to identify a potentially novel molecular mechanism through which MYC regulates the profile and function of the OS immune landscape.


Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , Humanos , Ratones , Animales , Macrófagos Asociados a Tumores/patología , Factor Estimulante de Colonias de Macrófagos/genética , Osteosarcoma/genética , Osteosarcoma/patología , Neoplasias Óseas/patología , MicroARNs/genética , Microambiente Tumoral/genética
20.
Cancer Med ; 12(1): 584-596, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-35676822

RESUMEN

BACKGROUND: Non-small cell lung cancer (NSCLC) comprises the majority (~85%) of all lung tumors, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being the most frequently diagnosed histological subtypes. Multi-modal omics profiling has been carried out in NSCLC, but no studies have yet reported a unique metabolite-related gene signature and altered metabolic pathways associated with LUAD and LUSC. METHODS: We integrated transcriptomics and metabolomics to analyze 30 human lung tumors and adjacent noncancerous tissues. Differential co-expression was used to identify modules of metabolites that were altered between normal and tumor. RESULTS: We identified unique metabolite-related gene signatures specific for LUAD and LUSC and key pathways aberrantly regulated at both transcriptional and metabolic levels. Differential co-expression analysis revealed that loss of coherence between metabolites in tumors is a major characteristic in both LUAD and LUSC. We identified one metabolic onco-module gained in LUAD, characterized by nine metabolites and 57 metabolic genes. Multi-omics integrative analysis revealed a 28 metabolic gene signature associated with poor survival in LUAD, with six metabolite-related genes as individual prognostic markers. CONCLUSIONS: We demonstrated the clinical utility of this integrated metabolic gene signature in LUAD by using it to guide repurposing of AZD-6482, a PI3Kß inhibitor which significantly inhibited three genes from the 28-gene signature. Overall, we have integrated metabolomics and transcriptomics analyses to show that LUAD and LUSC have distinct profiles, inferred gene signatures with prognostic value for patient survival, and identified therapeutic targets and repurposed drugs for potential use in NSCLC treatment.


Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Transcriptoma , Adenocarcinoma del Pulmón/genética , Perfilación de la Expresión Génica
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