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1.
Artículo en Inglés | MEDLINE | ID: mdl-38565264

RESUMEN

In this work, we review the multifaceted connections between osteosarcoma (OS) biology and normal bone development. We summarize and critically analyze existing research, highlighting key areas that merit further exploration. The review addresses several topics in OS biology and their interplay with normal bone development processes, including OS cell of origin, genomics, tumor microenvironment, and metastasis. We examine the potential cellular origins of OS and how their roles in normal bone growth may contribute to OS pathogenesis. We survey the genomic landscape of OS, highlighting the developmental roles of genes frequently altered in OS. We then discuss the OS microenvironment, emphasizing the transformation of the bone niche in OS to facilitate tumor growth and metastasis. The role of stromal and immune cells is examined, including their impact on tumor progression and therapeutic response. We further provide insights into potential development-informed opportunities for novel therapeutic strategies.

2.
Nat Chem Biol ; 20(1): 30-41, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37400538

RESUMEN

Ectodomain phosphatase/phosphodiesterase-1 (ENPP1) is overexpressed on cancer cells and functions as an innate immune checkpoint by hydrolyzing extracellular cyclic guanosine monophosphate adenosine monophosphate (cGAMP). Biologic inhibitors have not yet been reported and could have substantial therapeutic advantages over current small molecules because they can be recombinantly engineered into multifunctional formats and immunotherapies. Here we used phage and yeast display coupled with in cellulo evolution to generate variable heavy (VH) single-domain antibodies against ENPP1 and discovered a VH domain that allosterically inhibited the hydrolysis of cGAMP and adenosine triphosphate (ATP). We solved a 3.2 Å-resolution cryo-electron microscopy structure for the VH inhibitor complexed with ENPP1 that confirmed its new allosteric binding pose. Finally, we engineered the VH domain into multispecific formats and immunotherapies, including a bispecific fusion with an anti-PD-L1 checkpoint inhibitor that showed potent cellular activity.


Asunto(s)
Hidrolasas Diéster Fosfóricas , Anticuerpos de Dominio Único , Hidrolasas Diéster Fosfóricas/metabolismo , Monoéster Fosfórico Hidrolasas , Microscopía por Crioelectrón
3.
Clin Cancer Res ; 30(4): 849-864, 2024 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-37703185

RESUMEN

PURPOSE: Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, multiple models are needed to fully elucidate key aspects of disease biology and to recapitulate clinically relevant phenotypes. EXPERIMENTAL DESIGN: Matched patient samples, patient-derived xenografts (PDX), and PDX-derived cell lines were comprehensively evaluated using whole-genome sequencing and RNA sequencing. The in vivo metastatic phenotype of the PDX-derived cell lines was characterized in both an intravenous and an orthotopic murine model. As a proof-of-concept study, we tested the preclinical effectiveness of a cyclin-dependent kinase inhibitor on the growth of metastatic tumors in an orthotopic amputation model. RESULTS: PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication in a subset of cell lines. The cell lines were heterogeneous in their metastatic capacity, and heterogeneous tissue tropism was observed in both intravenous and orthotopic models. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden. CONCLUSIONS: The variation in metastasis predilection sites between osteosarcoma PDX-derived cell lines demonstrates their ability to recapitulate the spectrum of the disease observed in patients. We describe here a panel of new osteosarcoma PDX-derived cell lines that we believe will be of wide use to the osteosarcoma research community.


Asunto(s)
Neoplasias Óseas , Óxidos N-Cíclicos , Indolizinas , Osteosarcoma , Compuestos de Piridinio , Humanos , Animales , Ratones , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ensayos Antitumor por Modelo de Xenoinjerto , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Osteosarcoma/metabolismo , Línea Celular Tumoral , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo
4.
Cancer Rep (Hoboken) ; 6(12): e1901, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37933765

RESUMEN

BACKGROUND: The development of tyrosine kinase inhibitors (TKIs) has significantly improved survival rates among patients with Philadelphia chromosome (Ph+) B cell acute lymphoblastic leukemia (B-ALL). Ph-like B-ALL patients lack the BCR::ABL1 translocation but share gene expression profiles with Ph+ B-ALL. The role of TKIs for Ph-like patients pre- and post-hematopoietic stem cell transplantation (HSCT) is not yet clear. CASE: Here we present five cases of pediatric, adolescent, and young adult patients who presented with Ph-like B-ALL or CML in B-ALL blast phase who were treated with personalized TKI regimens pre- and post-HSCT. CONCLUSION: This report describes several novel Ph-like fusions as well as combinations of TKIs with chemotherapy or immunotherapy not yet reported in the pediatric population. This case series provides real-world experience highlighting the potential application of pre- and post-HSCT use of TKIs in a subset of patients with targetable fusions.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Adolescente , Adulto Joven , Inhibidores de Proteínas Quinasas/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos
5.
Res Sq ; 2023 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-37398210

RESUMEN

The genetic principle of synthetic lethality is clinically validated in cancers with loss of specific DNA damage response (DDR) pathway genes (i.e. BRCA1/2 tumor suppressor mutations). The broader question of whether and how oncogenes create tumor-specific vulnerabilities within DDR networks remains unanswered. Native FET protein family members are among the earliest proteins recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DSB repair remains poorly defined. Here we focus on Ewing sarcoma (ES), an EWS-FLI1 fusion oncoprotein-driven pediatric bone tumor, as a model for FET rearranged cancers. We discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native EWS function in activating the DNA damage sensor ATM. Using preclinical mechanistic approaches and clinical datasets, we establish functional ATM deficiency as a principal DNA repair defect in ES and the compensatory ATR signaling axis as a collateral dependency and therapeutic target in FET rearranged cancers. Thus, aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt normal DSB repair, revealing a mechanism for how oncogenes can create cancer-specific synthetic lethality within DDR networks.

6.
Nat Commun ; 14(1): 3966, 2023 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-37407562

RESUMEN

KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.


Asunto(s)
Adenocarcinoma del Pulmón , Proteínas Potenciadoras de Unión a CCAAT , Neoplasias Pulmonares , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ratones , Adenocarcinoma del Pulmón/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Transformación Celular Neoplásica/genética , Metilación de ADN , Epigénesis Genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
7.
bioRxiv ; 2023 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-37205599

RESUMEN

While oncogenes promote cancer cell growth, unrestrained proliferation represents a significant stressor to cellular homeostasis networks such as the DNA damage response (DDR). To enable oncogene tolerance, many cancers disable tumor suppressive DDR signaling through genetic loss of DDR pathways and downstream effectors (e.g., ATM or p53 tumor suppressor mutations). Whether and how oncogenes can help "self-tolerize" by creating analogous functional deficiencies in physiologic DDR networks is not known. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWS-FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET protein family members are among the earliest factors recruited to DNA double-strand breaks (DSBs) during the DDR, though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. Using preclinical mechanistic studies of the DDR and clinical genomic datasets from patient tumors, we discover that the EWS-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native FET (EWS) protein function in activating the DNA damage sensor ATM. As a consequence of FET fusion-mediated interference with the DDR, we establish functional ATM deficiency as the principal DNA repair defect in Ewing sarcoma and the compensatory ATR signaling axis as a collateral dependency and therapeutic target in multiple FET rearranged cancers. More generally, we find that aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt physiologic DSB repair, revealing a mechanism for how growth-promoting oncogenes can also create a functional deficiency within tumor suppressive DDR networks.

8.
Cancer Cell ; 41(4): 660-677.e7, 2023 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-37001527

RESUMEN

Pediatric solid and central nervous system tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient's disease. However, the generation and characterization of pediatric cancer models has significantly lagged behind adult cancers, underscoring the urgent need to develop pediatric-focused cell line resources. Herein, we establish a single-site collection of 261 cell lines, including 224 pediatric cell lines representing 18 distinct extracranial and brain childhood tumor types. We subjected 182 cell lines to multi-omics analyses (DNA sequencing, RNA sequencing, DNA methylation), and in parallel performed pharmacological and genetic CRISPR-Cas9 loss-of-function screens to identify pediatric-specific treatment opportunities and biomarkers. Our work provides insight into specific pathway vulnerabilities in molecularly defined pediatric tumor classes and uncovers biomarker-linked therapeutic opportunities of clinical relevance. Cell line data and resources are provided in an open access portal.


Asunto(s)
Neoplasias Encefálicas , Niño , Humanos , Neoplasias Encefálicas/patología , Línea Celular Tumoral
9.
bioRxiv ; 2023 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-36711882

RESUMEN

Models to study metastatic disease in rare cancers are needed to advance preclinical therapeutics and to gain insight into disease biology, especially for highly aggressive cancers with a propensity for metastatic spread. Osteosarcoma is a rare cancer with a complex genomic landscape in which outcomes for patients with metastatic disease are poor. As osteosarcoma genomes are highly heterogeneous, a large panel of models is needed to fully elucidate key aspects of disease biology and to recapitulate clinically-relevant phenotypes. We describe the development and characterization of osteosarcoma patient-derived xenografts (PDXs) and a panel of PDX-derived cell lines. Matched patient samples, PDXs, and PDX-derived cell lines were comprehensively evaluated using whole genome sequencing and RNA sequencing. PDXs and PDX-derived cell lines largely maintained the expression profiles of the patient from which they were derived despite the emergence of whole-genome duplication (WGD) in a subset of cell lines. These cell line models were heterogeneous in their metastatic capacity and their tissue tropism as observed in both intravenous and orthotopic models. As proof-of-concept study, we used one of these models to test the preclinical effectiveness of a CDK inhibitor on the growth of metastatic tumors in an orthotopic amputation model. Single-agent dinaciclib was effective at dramatically reducing the metastatic burden in this model.

10.
Genome Med ; 14(1): 124, 2022 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-36316687

RESUMEN

BACKGROUND: Ganciclovir (GCV) is widely used in solid organ and haematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. METHODS: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. RESULTS: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCVsig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. CONCLUSIONS: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.


Asunto(s)
Infecciones por Citomegalovirus , Ganciclovir , Neoplasias , Humanos , Antivirales/efectos adversos , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/prevención & control , Ganciclovir/efectos adversos , Inmunosupresores/efectos adversos , Mutación , Neoplasias/inducido químicamente , Neoplasias/genética , Estudios Retrospectivos
11.
Nat Commun ; 13(1): 4878, 2022 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-36008377

RESUMEN

Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.


Asunto(s)
Hepatoblastoma , Neoplasias Hepáticas , Quimioterapia Adyuvante , Niño , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/genética , Humanos , Lactante , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Medicina de Precisión , Análisis de la Célula Individual
12.
Cancers (Basel) ; 14(12)2022 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-35740503

RESUMEN

Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.

13.
Adv Healthc Mater ; 11(17): e2200768, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35767377

RESUMEN

Osteosarcoma (OS) is an aggressive bone cancer for which survival has not improved over three decades. While biomaterials have been widely used to engineer 3D soft-tissue tumor models, the potential of engineering 3D biomaterials-based OS models for comprehensive interrogation of OS pathology and drug discovery remains untapped. Bone is characterized by high mineral content, yet the role of bone mineral in OS progression and drug response remains unknown. Here, a microribbon-based OS model with bone-mimicking compositions is developed to elucidate the role of 3D culture and hydroxyapatite in OS signaling and drug response. The results reveal that hydroxyapatite in 3D is critical to support retention of OS signaling and drug resistance similar to patient tissues and mouse orthotopic tumors. The physiological relevance of this 3D model is validated using four established OS cell lines, seven patient-derived xenograft (PDX) cell lines and two animal models. Integrating 3D OS PDX models with RNA-sequencing identified 3D-specific druggable target, which predicts drug response in mouse orthotopic model. These results establish microribbon-based 3D OS models as a novel experimental tool to enable discovery of novel therapeutics that would be otherwise missed with 2D model and may serve as platforms to study patient-specific OS heterogeneity and drug resistance mechanisms.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Animales , Materiales Biocompatibles , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Señales (Psicología) , Descubrimiento de Drogas , Humanos , Hidroxiapatitas , Ratones , Minerales , Osteosarcoma/patología
14.
Mol Cell Proteomics ; 21(7): 100247, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35594991

RESUMEN

Since the discovery of oncogenes, there has been tremendous interest to understand their mechanistic basis and to develop broadly actionable therapeutics. Some of the most frequently activated oncogenes driving diverse cancers are c-MYC, EGFR, HER2, AKT, KRAS, BRAF, and MEK. Using a reductionist approach, we explored how cellular proteomes are remodeled in isogenic cell lines engineered with or without these driver oncogenes. The most striking discovery for all oncogenic models was the systematic downregulation of scores of antiviral proteins regulated by type 1 interferon. These findings extended to cancer cell lines and patient-derived xenograft models of highly refractory pancreatic cancer and osteosarcoma driven by KRAS and MYC oncogenes. The oncogenes reduced basal expression of and autocrine stimulation by type 1 interferon causing remarkable convergence on common phenotypic and functional profiles. In particular, there was dramatically lower expression of dsRNA sensors including DDX58 (RIG-I) and OAS proteins, which resulted in attenuated functional responses when the oncogenic cells were treated with the dsRNA mimetic, polyI:C, and increased susceptibility to infection with an RNA virus shown using SARS-CoV-2. Our reductionist approach provides molecular and functional insights connected to immune evasion hallmarks in cancers and suggests therapeutic opportunities.


Asunto(s)
COVID-19 , Interferón beta , Oncogenes , Proteómica , Animales , Factores de Restricción Antivirales , COVID-19/inmunología , Carcinogénesis , Línea Celular Tumoral , Humanos , Interferón beta/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , SARS-CoV-2
15.
Salud Publica Mex ; 64(1): 100-104, 2022 Feb 25.
Artículo en Español | MEDLINE | ID: mdl-35438915

RESUMEN

In 2014, a partnership was established between the Univer-sity of California and Mexico, which subsequently catalyzed formation of collaborations between cancer researchers at University of California, San Francisco and in Mexico. Over the past two decades cancer burden has dramatically increased in Mexicans on both sides of the California - Mexico border. Together, we face a growing burden of cancer in the context of globalized economies, diverse migration patterns, and dynamic immigration policies. Our partnership aims to: (1) understand the life course impact of cancer risk factors and interactions with changing environments; (2) address cancer disparities within Mexico, in Mexican migrants to the United States, and in naturalized Mexican-Americans; and (3) identify effective cancer screening strategies and cancer control policies that are tailored to existing healthcare systems and social and cultural factors. Herein, we describe the principles of partner-ship and early successes and challenges of this collaboration.


Asunto(s)
Neoplasias , Migrantes , Atención a la Salud , Emigración e Inmigración , Humanos , Americanos Mexicanos , México/epidemiología , Neoplasias/epidemiología , Estados Unidos
16.
Salud pública Méx ; 64(1): 100-104, ene.-feb. 2022. tab
Artículo en Inglés | LILACS-Express | LILACS | ID: biblio-1432354

RESUMEN

Abstract: In 2014, a partnership was established between the University of California and Mexico, which subsequently catalyzed formation of collaborations between cancer researchers at University of California, San Francisco and in Mexico. Over the past two decades cancer burden has dramatically increased in Mexicans on both sides of the California - Mexico border. Together, we face a growing burden of cancer in the context of globalized economies, diverse migration patterns, and dynamic immigration policies. Our partnership aims to: 1) understand the life course impact of cancer risk factors and interactions with changing environments; 2) address cancer disparities within Mexico, in Mexican migrants to the United States, and in naturalized Mexican-Americans; and 3) identify effective cancer screening strategies and cancer control policies that are tailored to existing healthcare systems and social and cultural factors. Herein, we describe the principles of partnership and early successes and challenges of this collaboration.


Resumen: En 2014, se estableció un convenio de colaboración colaboración entre la Universidad de California y México, que posteriormente catalizó colaboraciones específicas entre investigadores en cáncer en la Universidad de California, San Francisco y en México. En las últimas dos décadas, la carga del cáncer ha aumentado drásticamente en mexicanos de ambos lados de la frontera entre California y México. Juntos, enfrentamos una carga creciente de cáncer en un contexto de economías globalizadas y diversos patrones y políticas de migración dinámicas. Nuestra colaboración tiene como objetivo: 1) entender el impacto a lo largo de la vida de factores de riesgo de cáncer y sus interacciones en un entorno cambiante; 2) abordar disparidades del cáncer dentro de México, en os migrantes mexicanos a los Estados Unidos y en los mexicoamericanos naturalizados; y 3) identificar estrategias efectivas de detección del cáncer y políticas de control del cáncer que se adapten a sistemas de salud existentes y a factores sociales y culturales. Aquí describimos los principios de esta colaboración y los primeros éxitos y retos de la misma.

17.
Cancers (Basel) ; 13(24)2021 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-34944883

RESUMEN

Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.

18.
Mol Cancer Ther ; 20(10): 2016-2025, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34353895

RESUMEN

Most circulating tumor DNA (ctDNA) assays are designed to detect recurrent mutations. Pediatric sarcomas share few recurrent mutations but rather are characterized by translocations and copy-number changes. We applied Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) for detection of translocations found in the most common pediatric sarcomas. We also applied ichorCNA to the combined off-target reads from our hybrid capture to simultaneously detect copy-number alterations (CNA). We analyzed 64 prospectively collected plasma samples from 17 patients with pediatric sarcoma. Translocations were detected in the pretreatment plasma of 13 patients and were confirmed by tumor sequencing in 12 patients. Two of these patients had evidence of complex chromosomal rearrangements in their ctDNA. We also detected copy-number changes in the pretreatment plasma of 7 patients. We found that ctDNA levels correlated with metastatic status and clinical response. Furthermore, we detected rising ctDNA levels before relapse was clinically apparent, demonstrating the high sensitivity of our assay. This assay can be utilized for simultaneous detection of translocations and CNAs in the plasma of patients with pediatric sarcoma. While we describe our experience in pediatric sarcomas, this approach can be applied to other tumors that are driven by structural variants.


Asunto(s)
Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Variaciones en el Número de Copia de ADN , ADN de Neoplasias/genética , Recurrencia Local de Neoplasia/diagnóstico , Sarcoma/diagnóstico , Translocación Genética , Biomarcadores de Tumor/sangre , Niño , ADN Tumoral Circulante/sangre , ADN de Neoplasias/sangre , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estudios Longitudinales , Mutación , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Pronóstico , Estudios Prospectivos , Sarcoma/genética , Sarcoma/metabolismo
19.
J Pediatr Hematol Oncol ; 43(6): e808-e811, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32815876

RESUMEN

Overlapping myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders with features of myelodysplasia and myeloproliferation. The only well-characterized MDS/MPN in children is juvenile myelomonocytic leukemia, an aggressive disorder of infants and toddlers. The biochemical hallmark of this disease is hyperactivation of the Ras/MAPK signaling pathway caused by mutations in Ras pathway genes in more than 90% of patients. Translocations involving receptor tyrosine kinases have been identified in rare cases. Here, we report a 2-year-old patient who presented with MDS/MPN driven by a cytogenetically cryptic NUP98-NSD1 fusion, a translocation thought to exclusively occur in patients with acute myeloid leukemia.


Asunto(s)
Leucemia Mielomonocítica Juvenil/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Proteínas de Fusión Oncogénica/genética , Preescolar , Citogenética , Femenino , Humanos , Leucemia Mielomonocítica Juvenil/diagnóstico , Enfermedades Mielodisplásicas-Mieloproliferativas/diagnóstico , Translocación Genética
20.
Nat Biotechnol ; 39(2): 215-224, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32929263

RESUMEN

Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence sources-including protein structure, gene expression and mutational profiles-via the OncoSig machine learning framework. We first generated a KRAS-specific SigMap for lung adenocarcinoma, which recapitulated published KRAS biology, identified novel synthetic lethal proteins that were experimentally validated in three-dimensional spheroid models and established uncharacterized crosstalk with RAB/RHO. To show that OncoSig is generalizable, we first inferred SigMaps for the ten most mutated human oncoproteins and then for the full repertoire of 715 proteins in the COSMIC Cancer Gene Census. Taken together, these SigMaps show that the cell's regulatory and signaling architecture is highly tissue specific.


Asunto(s)
Redes Reguladoras de Genes , Neoplasias/genética , Proteínas Oncogénicas/metabolismo , Algoritmos , Animales , Humanos , Ratones , Mutación/genética , Organoides/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , ARN Interferente Pequeño/metabolismo , Curva ROC , Transducción de Señal
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