RESUMEN
CD8+ T cell dysfunction impedes antitumor immunity in solid cancers, but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional coactivator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In turn, COLVI induces CD8+ T cell dysfunction and immune evasion by remodeling fibrillar collagen and inhibiting T cell autophagic flux. Unexpectedly, collagen I (COLI) opposed COLVI in this setting, promoting CD8+ T cell function and acting as a tumor suppressor. Thus, CD8+ T cell responses in sarcoma depend on oncogene-mediated ECM composition and remodeling.
Asunto(s)
Linfocitos T CD8-positivos , Matriz Extracelular , Sarcoma , Microambiente Tumoral , Proteínas Señalizadoras YAP , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Animales , Microambiente Tumoral/inmunología , Ratones , Proteínas Señalizadoras YAP/inmunología , Proteínas Señalizadoras YAP/genética , Humanos , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Sarcoma/inmunología , Sarcoma/patología , Sarcoma/genética , Sarcoma/metabolismo , Colágeno Tipo VI/genética , Colágeno Tipo VI/inmunología , Colágeno Tipo VI/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/inmunología , Oncogenes , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Colágeno Tipo I/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/inmunologíaRESUMEN
Globally, hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related death. We previously identified an immune evasion pathway whereby tumor cells produce retinoic acid (RA) to promote differentiation of intratumoral monocytes into protumor macrophages. Retinaldehyde dehydrogenase 1 (RALDH1), RALDH2, and RALDH3 are the three isozymes that catalyze RA biosynthesis. In this study, we have identified RALDH1 as the key driver of RA production in HCC and demonstrated the efficacy of RALDH1-selective inhibitors (Raldh1-INH) in suppressing RA production by HCC cells. Raldh1-INH restrained tumor growth in multiple mouse models of HCC by reducing the number and tumor-supporting functions of intratumoral macrophages as well as increasing T-cell infiltration and activation within tumors. Raldh1-INH also displayed favorable pharmacokinetic, pharmacodynamic, and toxicity profiles in mice thereby establishing them as promising new drug candidates for HCC immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Ratones , Animales , Retinal-Deshidrogenasa/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Tretinoina/farmacología , Tretinoina/metabolismo , Aldehído Oxidorreductasas/metabolismoRESUMEN
The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire immunosuppressive and pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.
Asunto(s)
Carcinoma , Neoplasias Colorrectales , Animales , Ratones , Humanos , Microambiente Tumoral/genética , Macrófagos/metabolismo , Carcinogénesis/patología , Neoplasias Colorrectales/metabolismo , Carcinoma/metabolismoRESUMEN
In this issue of Developmental Cell, Pokrajac et al. report that Wnt signaling in endothelial cells maintain CXCL4 expression in meningeal macrophages, which suppresses induction of Sonic hedgehog medulloblastoma by antagonizing the pro-tumor effects of CXCL12. This work highlights how homeostatic tissue macrophages can regulate early stages of tumor induction.
Asunto(s)
Neoplasias Cerebelosas , Meduloblastoma , Humanos , Meduloblastoma/metabolismo , Células Endoteliales/metabolismo , Proteínas Hedgehog/metabolismo , Macrófagos/metabolismoRESUMEN
SIGNIFICANCE: Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to ß-catenin-driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.
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Neoplasias de la Mama , Fibroblastos Asociados al Cáncer , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Fibroblastos Asociados al Cáncer/patología , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular , Ligandos , Receptores Notch , beta CateninaRESUMEN
Current single-cell RNA sequencing (scRNA-seq) protocols are limited by the number of cells that can be simultaneously sequenced, restricting the ability to resolve heterogeneity of rare cell types. We describe here a protocol for rapid isolation of myeloid cells from tumor-harboring mouse cerebellum without cell sorting to minimize cell damage for scRNA-seq. This protocol includes the procedures for further enrichment of myeloid cells using CD11b+ magnetic beads, followed by the generation of scRNA library and sequencing analysis. For complete details on the use and execution of this protocol, please refer to Dang et al. (2021).
Asunto(s)
Neoplasias Encefálicas/patología , Separación Celular/métodos , Células Mieloides/citología , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Animales , Encéfalo/citología , Masculino , Ratones , Ratones TransgénicosRESUMEN
Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure. Rather, it was induced by the excessive loss of lipids through the skin as sebum. TSLP and T cells regulated sebum release and sebum-associated antimicrobial peptide expression in the steady state. In human skin, TSLP expression correlated directly with sebum-associated gene expression. Thus, we establish a paradigm in which adipose loss can be achieved by means of sebum hypersecretion and uncover a role for adaptive immunity in skin barrier function through sebum secretion.
Asunto(s)
Tejido Adiposo Blanco/anatomía & histología , Citocinas/metabolismo , Sebo/metabolismo , Piel/metabolismo , Inmunidad Adaptativa , Animales , Citocinas/genética , Dieta , Glucosa/metabolismo , Homeostasis , Humanos , Inmunoglobulinas/metabolismo , Metabolismo de los Lípidos , Ratones , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/prevención & control , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Receptores de Citocinas/metabolismo , Glándulas Sebáceas/metabolismo , Transducción de Señal , Piel/inmunología , Linfocitos T/fisiología , Pérdida de Peso , Linfopoyetina del Estroma TímicoRESUMEN
Tumor-associated macrophages (TAMs) play an important role in tumor immunity and comprise of subsets that have distinct phenotype, function, and ontology. Transcriptomic analyses of human medulloblastoma, the most common malignant pediatric brain cancer, showed that medulloblastomas (MBs) with activated sonic hedgehog signaling (SHH-MB) have significantly more TAMs than other MB subtypes. Therefore, we examined MB-associated TAMs by single-cell RNA sequencing of autochthonous murine SHH-MB at steady state and under two distinct treatment modalities: molecular-targeted inhibitor and radiation. Our analyses reveal significant TAM heterogeneity, identify markers of ontologically distinct TAM subsets, and show the impact of brain microenvironment on the differentiation of tumor-infiltrating monocytes. TAM composition undergoes dramatic changes with treatment and differs significantly between molecular-targeted and radiation therapy. We identify an immunosuppressive monocyte-derived TAM subset that emerges with radiation therapy and demonstrate its role in regulating T cell and neutrophil infiltration in MB.
Asunto(s)
Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/terapia , Proteínas Hedgehog/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Meduloblastoma/patología , Meduloblastoma/terapia , Animales , Linfocitos T CD8-positivos/inmunología , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/inmunología , Marcadores Genéticos , Humanos , Meduloblastoma/genética , Meduloblastoma/inmunología , Ratones , Microglía/patología , Monocitos/patología , Análisis de la Célula Individual , Transcripción Genética , Microambiente TumoralRESUMEN
The regulation of monocyte differentiation in the tumor microenvironment is of significant interest to tumor immunologists. Monocytes injected into the circulation may not track into tumors in sufficient numbers, making intratumoral injections a preferred experimental approach. Monocyte enrichment with antibody-based positive selection may activate downstream signaling, while cell sorters expose monocytes to mechanical stress. Here, we describe an approach of intratumoral monocyte transfer that circumvents these limitations by using negative selection and fluorescent reporter mice. For complete details on the use and execution of this protocol, please refer to Devalaraja et al. (2020).
Asunto(s)
Diferenciación Celular , Monocitos/patología , Neoplasias/patología , Microambiente Tumoral , Animales , Femenino , Masculino , Ratones Endogámicos C57BL , MicroesferasRESUMEN
Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this "balancing act" remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a "default" Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Inflamación/metabolismo , Inflamación/patología , Hierro/metabolismo , Macrófagos/metabolismo , FN-kappa B/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Animales , Transporte Biológico , Regulación hacia Abajo/genética , Femenino , Hemo/metabolismo , Interferón gamma/metabolismo , Ligandos , Activación de Macrófagos , Masculino , Ratones Endogámicos C57BL , Monocitos/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we find that the TME induces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocyte differentiation toward TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade. Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple human tumors. RA has been considered as an anti-cancer agent, whereas our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
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Monocitos/inmunología , Tretinoina/metabolismo , Microambiente Tumoral/inmunología , Animales , Carcinogénesis/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/inmunología , Línea Celular Tumoral , Células Dendríticas/inmunología , Humanos , Terapia de Inmunosupresión/métodos , Inmunoterapia/métodos , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismoRESUMEN
High-grade sarcomas are metastatic and pose a serious threat to patient survival. Undifferentiated pleomorphic sarcoma (UPS) is a particularly dangerous and relatively common sarcoma subtype diagnosed in adults. UPS contains large quantities of extracellular matrix (ECM) including hyaluronic acid (HA), which is linked to metastatic potential. Consistent with these observations, expression of the HA receptor, hyaluronan-mediated motility receptor (HMMR/RHAMM), is tightly controlled in normal tissues and upregulated in UPS. Moreover, HMMR expression correlates with poor clinical outcome in these patients. Deregulation of the tumor-suppressive Hippo pathway is also linked to poor outcome in these patients. YAP1, the transcriptional regulator and central effector of Hippo pathway, is aberrantly stabilized in UPS and was recently shown to control RHAMM expression in breast cancer cells. Interestingly, both YAP1 and RHAMM are linked to TGFß signaling. Therefore, we investigated crosstalk between YAP1 and TGFß resulting in enhanced RHAMM-mediated cell migration and invasion. We observed that HMMR expression is under the control of both YAP1 and TGFß and can be effectively targeted with small-molecule approaches that inhibit these pathways. Furthermore, we found that RHAMM expression promotes tumor cell proliferation and migration/invasion. To test these observations in a robust and quantifiable in vivo system, we developed a zebrafish xenograft assay of metastasis, which is complimentary to our murine studies. Importantly, pharmacologic inhibition of the TGFß-YAP1-RHAMM axis prevents vascular migration of tumor cells to distant sites. IMPLICATIONS: These studies reveal key metastatic signaling mechanisms and highlight potential approaches to prevent metastatic dissemination in UPS.YAP1 and TGFß cooperatively enhance proliferation and migration/invasion of UPS and fibrosarcomas.
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Proteínas de la Matriz Extracelular/metabolismo , Receptores de Hialuranos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Sarcoma/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Animales Modificados Genéticamente , Línea Celular Tumoral , Fibrosarcoma , Células HCT116 , Células HEK293 , Vía de Señalización Hippo , Humanos , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Sarcoma/patología , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP , Pez CebraRESUMEN
Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter SLC48A1 (also known as HRG1) accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal. Macrophages tolerate these high concentrations of heme by crystallizing them into hemozoin, which heretofore has only been found in blood-feeding organisms. SLC48A1 deficiency results in impaired erythroid maturation and an inability to systemically respond to iron deficiency. Complete heme tolerance requires a fully-operational heme degradation pathway as haplo insufficiency of HMOX1 combined with SLC48A1 inactivation causes perinatal lethality demonstrating synthetic lethal interactions between heme transport and degradation. Our studies establish the formation of hemozoin by mammals as a previously unsuspected heme tolerance pathway.
Specialized cells, known as red blood cells, are responsible for transporting oxygen to various organs in the body. Each red blood cell contains over a billion molecules of heme which make up the iron containing portion of the hemoglobin protein that binds and transports oxygen. When red blood cells reach the end of their life, they are degraded, and the heme and iron inside them is recycled to produce new red blood cells. Heme, however, is highly toxic to cells, and can cause severe tissue damage if not properly removed. Scavenger cells called macrophages perform this recycling role in the spleen, liver and bone marrow. Collectively, macrophages can process around five million red blood cells every second or about 100 trillion heme molecules. But, it is unclear how they are able to handle such enormous volumes. Macrophages isolated from human and mice have been shown to transport heme from damaged red blood cells using a protein called HRG1. To investigate the role HRG1 plays in heme-iron recycling, Pek et al. used a gene editing tool known an CRISPR/Cas9 to remove the gene for HRG1 from the macrophages of mice. If HRG1 is a major part of this process, removing the gene should result in a build-up of toxic heme and eventual death of the mouse. But, rather than dying of heme-iron overload as expected, these mutant mice managed to survive. Pek et al. found that despite being unable to recycle heme, these mice were still able to make new red blood cells as long as they had a diet that was rich in iron. However, the darkening color of the spleen, bone marrow, and liver in these HRG1 deficient mice indicated that these mice were still accumulating high levels of heme. Further experiments revealed that these mice protected themselves from toxicity by converting the excess heme into crystals called hemozoin. This method of detoxification is commonly seen in blood-feeding parasites, and this is the first time it has been observed in a mammal. These crystals invite new questions about how mammals recycle heme and what happens when this process goes wrong. The next step is to ask whether humans also start to make hemozoin if the gene for HRG1 is faulty. If so, this could open a new avenue of exploration into treatments for red blood cell diseases like anemia and iron overload.
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Hemo/toxicidad , Hemoproteínas/metabolismo , Macrófagos/metabolismo , Animales , Hemo-Oxigenasa 1/metabolismo , Hemoproteínas/deficiencia , Proteínas de la Membrana/metabolismo , RatonesRESUMEN
Primary malignant bone tumors are rare, occur in all age groups, and include distinct entities such as osteosarcoma, Ewing sarcoma, and chondrosarcoma. Traditional treatment with some combination of chemotherapy, surgery, and radiation has reached the limit of efficacy, with substantial room for improvement in patient outcome. Furthermore, genomic characterization of these tumors reveals a paucity of actionable molecular targets. Against this backdrop, recent advances in cancer immunotherapy represent a silver lining in the treatment of primary bone cancer. Major strategies in cancer immunotherapy include stimulating naturally occurring anti-tumor T cells and adoptive transfer of tumor-specific cytotoxic T cells. Chimeric antigen receptor T cells (CAR-T cells) belong to the latter strategy and are an impressive application of both insights into T cell biology and advances in genetic engineering. In this review, we briefly describe the CAR-T approach and discuss its applications in primary bone tumors. © 2019 American Society for Bone and Mineral Research.
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Neoplasias Óseas/terapia , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos/uso terapéutico , Neoplasias Óseas/inmunología , Humanos , Receptores de Antígenos de Linfocitos T/química , Receptores de Antígenos de Linfocitos T/metabolismoRESUMEN
Nearly two-thirds of cancer patients are treated with radiation therapy (RT), often with the intent to achieve complete and permanent tumor regression (local control). RT is the primary treatment modality used to achieve local control for many malignancies, including locally advanced cervical cancer, head and neck cancer, and lung cancer. The addition of concurrent platinum-based radiosensitizing chemotherapy improves local control and patient survival. Enhanced outcomes with concurrent chemoradiotherapy may result from increased direct killing of tumor cells and effects on nontumor cell populations. Many patients treated with concurrent chemoradiotherapy exhibit a decline in neutrophil count, but the effects of neutrophils on radiation therapy are controversial. To investigate the clinical significance of neutrophils in the response to RT, we examined patient outcomes and circulating neutrophil counts in cervical cancer patients treated with definitive chemoradiation. Although pretreatment neutrophil count did not correlate with outcome, lower absolute neutrophil count after starting concurrent chemoradiotherapy was associated with higher rates of local control, metastasis-free survival, and overall survival. To define the role of neutrophils in tumor response to RT, we used genetic and pharmacological approaches to deplete neutrophils in an autochthonous mouse model of soft tissue sarcoma. Neutrophil depletion prior to image-guided focal irradiation improved tumor response to RT. Our results indicate that neutrophils promote resistance to radiation therapy. The efficacy of chemoradiotherapy may depend on the impact of treatment on peripheral neutrophil count, which has the potential to serve as an inexpensive and widely available biomarker.
Asunto(s)
Quimioradioterapia , Neutrófilos/inmunología , Tolerancia a Radiación/inmunología , Sarcoma/terapia , Neoplasias del Cuello Uterino/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Modelos Animales de Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Recuento de Leucocitos , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Tolerancia a Radiación/genética , Estudios Retrospectivos , Sarcoma/sangre , Sarcoma/inmunología , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/mortalidad , Irradiación Corporal Total , Adulto JovenRESUMEN
To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFκB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFκB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment.Significance: A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Cancer Res; 78(10); 2705-20. ©2018 AACR.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transformación Celular Neoplásica/patología , FN-kappa B/metabolismo , Fosfoproteínas/metabolismo , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Proteasas Ubiquitina-Específicas/antagonistas & inhibidores , Proteasas Ubiquitina-Específicas/biosíntesis , Angiomotinas , Animales , Antineoplásicos/farmacología , Azepinas/farmacología , Proteínas de Ciclo Celular , Línea Celular Tumoral , Transformación Celular Neoplásica/genética , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos/genética , Músculo Esquelético/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Sarcoma/genética , Transducción de Señal/genética , Neoplasias de los Tejidos Blandos/genética , Factores de Transcripción , Triazoles/farmacología , Vorinostat/farmacología , Proteínas Señalizadoras YAPRESUMEN
Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5-expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of ß-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2-transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX-driven oncogenesis in cells as differentiated as preosteoblasts.