RESUMEN
Objective: To investigate the benefits and drawbacks of breast reconstruction with endoscopic-assisted harvesting of the latissimus dorsi muscle flap for breast cancer and treatment experience of postoperative operation-related complications. Methods: A retrospective analysis was performed on clinical data of 26 female patients with breast cancer who met the selection criteria between September 2021 and March 2023 aging 48.7 years (range, 26-69 years). All tumors were unilateral, with 17 on the left side and 9 on the right side. The tumor size ranged from 1.0 to 7.0 cm, with an average of 2.7 cm. The pathological staging included T 1 in 11 cases, T 2 in 14 cases, and T 3 in 1 case; N 0 in 10 cases, N 1 in 11 cases, N 2 in 2 cases, and N 3 in 3 cases; no distant metastasis (M 0) occurred when first diagnosed. Among them, 10 cases underwent breast conserving surgery, and 16 cases underwent nipple-sparing mastectomy. All patients underwent breast reconstruction with endoscopic-assisted harvesting of the latissimus dorsi muscle flap. The operation time, incision length, and postoperative drainage volume in 3 days were recorded. Breast-Q "Satisfaction with back" scale was conducted to evaluate patients' satisfaction with back at 6 months after operation. Results: The operation time was 280-480 minutes (mean, 376.7 minutes), the incision length was 10-15 cm (mean, 12.2 cm), the postoperative drainage volume in 3 days was 500-1 600 mL (mean, 930.2 mL). There were 4 cases of postoperative seroma, 1 case of incision rupture, 1 case of paresthesia of the thoracic wall, and 1 case of edema of the ipsilateral upper limb. All patients were followed up 12-30 months (mean, 20.1 months). No latissimus dorsi muscle flap necrosis, latissimus dorsi muscle atrophy, or shoulder joint dysfunction occurred during follow-up; 2 patients had recurrence of lymph nodes in the ipsilateral axilla after operation, but no distant metastasis occurred. Breast-Q score at 6 months after operation was 64-100 (mean, 79.5). The average score was 78.6 (range, 64-100) in patients underwent nipple-sparing mastectomy and 81.0 (range, 78-100) in patients underwent breast conserving surgery. Conclusion: Breast reconstruction with endoscopic-assisted harvesting of the latissimus dorsi muscle flap for breast cancer is proven to be a surgical approach with safety and cosmetic effects with mild postoperative operation-related complications and considerable patient satisfaction.
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Neoplasias de la Mama , Endoscopía , Mamoplastia , Complicaciones Posoperatorias , Músculos Superficiales de la Espalda , Colgajos Quirúrgicos , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/patología , Mamoplastia/métodos , Adulto , Estudios Retrospectivos , Músculos Superficiales de la Espalda/trasplante , Endoscopía/métodos , Anciano , Mastectomía/métodos , Mastectomía Segmentaria/métodosRESUMEN
Tumors employ various strategies to evade immune surveillance. Central nervous system (CNS) has multiple features to restrain immune response. Whether tumors and CNS share similar programs of immunosuppression is elusive. Here, we analyze multi-omics data of tumors from HER2+ breast cancer patients receiving trastuzumab and anti-PD-L1 antibody and find that CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are overexpressed in resistant tumors. In CNS, NAA is released during brain inflammation. NAT8L attenuates brain inflammation and impairs anti-tumor immunity by inhibiting cytotoxicity of natural killer (NK) cells and CD8+ T cells via NAA. NAA disrupts the formation of immunological synapse by promoting PCAF-induced acetylation of lamin A-K542, which inhibits the integration between lamin A and SUN2 and impairs polarization of lytic granules. We uncover that tumor cells mimic the anti-inflammatory mechanism of CNS to evade anti-tumor immunity and NAT8L is a potential target to enhance efficacy of anti-cancer agents.
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Sinapsis Inmunológicas , Humanos , Sinapsis Inmunológicas/metabolismo , Animales , Ratones , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/inmunología , Femenino , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Línea Celular Tumoral , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológicoRESUMEN
Emerging evidence has demonstrated the significant contribution of mitochondrial metabolism dysfunction to promote cancer development and progression. Aberrant expression of mitochondrial genome (mtDNA)-encoded proteins widely involves mitochondrial metabolism dysfunction, and targeted regulation of their expression can be an effective strategy for cancer therapy, which however is challenged due to the protection by the mitochondrial double membrane. Herein, a mitochondria-targeted RNAi nanoparticle (NP) platform for effective regulation of mitochondrial metabolism and breast cancer (BCa) therapy is developed. This nanoplatform is composed of a hydrophilic polyethylene glycol (PEG) shell, a hydrophobic poly(2-(diisopropylamino)ethyl methacrylate) (PDPA) core, and charged-mediated complexes of mitochondria-targeting and membrane-penetrating peptide amphiphile (MMPA) and small interfering RNA (siRNA) embedded in the core. After tumor accumulation and internalization by tumor cells, these NPs can respond to the endosomal pH to expose the MMPA/siRNA complexes, which can specifically transport siRNA into the mitochondria to down-regulate mtDNA-encoded protein expression (e.g., ATP6 and CYB). More importantly, because ATP6 down-regulation can suppress ATP production and enhance reactive oxygen species (ROS) generation to induce mitochondrial damage and mtDNA leakage into tumor tissues, the NPs can combinatorially inhibit tumor growth via suppressing ATP production and repolarizing tumor-associated macrophages (TAMs) into tumor-inhibiting M1-like macrophages by mtDNA.
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Neoplasias de la Mama , Nanopartículas , Propionatos , Compuestos de Sulfhidrilo , Humanos , Femenino , Interferencia de ARN , Neoplasias de la Mama/patología , ARN Interferente Pequeño/genética , Nanopartículas/química , Péptidos/metabolismo , Mitocondrias/metabolismo , ADN Mitocondrial , Adenosina Trifosfato , Línea Celular TumoralRESUMEN
Emerging data have shown that previously defined noncoding genomes might encode peptides that bind human leukocyte antigen (HLA) as cryptic antigens to stimulate adaptive immunity1,2. However, the significance and mechanisms of action of cryptic antigens in anti-tumour immunity remain unclear. Here mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I-binding cryptic antigenic peptides that were noncanonically translated by a tumour-specific circular RNA (circRNA): circFAM53B. The cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen-specific cytotoxic T cells, which led to effective tumour control. Overall, our findings reveal that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.
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Neoplasias de la Mama , Melanoma , Péptidos , Biosíntesis de Proteínas , ARN Circular , Animales , Femenino , Humanos , Ratones , Antígenos de Neoplasias/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Espectrometría de Masas , Melanoma/genética , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/patología , Péptidos/genética , Péptidos/inmunología , Perfilado de Ribosomas , ARN Circular/genética , ARN Circular/metabolismo , Análisis de SupervivenciaRESUMEN
Tumor-associated hydrocephalus (TAH) is a common and lethal complication of brain metastases. Although other factors beyond mechanical obstructions have been suggested, the exact mechanisms are unknown. Using single-nucleus RNA sequencing and spatial transcriptomics, we find that a distinct population of mast cells locate in the choroid plexus and dramatically increase during TAH. Genetic fate tracing and intracranial mast-cell-specific tryptase knockout showed that choroid plexus mast cells (CPMCs) disrupt cilia of choroid plexus epithelia via the tryptase-PAR2-FoxJ1 pathway and consequently increase cerebrospinal fluid production. Mast cells are also found in the human choroid plexus. Levels of tryptase in cerebrospinal fluid are closely associated with clinical severity of TAH. BMS-262084, an inhibitor of tryptase, can cross the blood-brain barrier, inhibit TAH in vivo, and alleviate mast-cell-induced damage of epithelial cilia in a human pluripotent stem-cell-derived choroid plexus organoid model. Collectively, we uncover the function of CPMCs and provide an attractive therapy for TAH.
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Neoplasias Encefálicas , Plexo Coroideo , Hidrocefalia , Mastocitos , Humanos , Neoplasias Encefálicas/secundario , Plexo Coroideo/metabolismo , Plexo Coroideo/patología , Hidrocefalia/metabolismo , Hidrocefalia/patología , Mastocitos/metabolismo , Mastocitos/patología , Triptasas/líquido cefalorraquídeo , Metástasis de la Neoplasia/patologíaRESUMEN
Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.
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Neoplasias de la Mama , Mecanotransducción Celular , Proteína Homeótica Nanog , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proteína Homeótica Nanog/genética , Células Madre Neoplásicas/patología , Factores de Transcripción/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ/genética , Nicho de Células MadreAsunto(s)
Inmunoterapia , Neoplasias , Humanos , Neoplasias/terapia , Linfocitos , Microambiente TumoralRESUMEN
Emerging lines of evidence have shown that the production of the covalently closed single-stranded circular RNAs is not splicing errors, but rather a regulated process with distinct biogenesis and turnover. Circular RNAs are expressed in a cell type- and tissue-specific manner and often localize to specific subcellular regions or organelles for functions. The dysregulation of circular RNAs from birth to death is linked to the pathogenesis and progression of diverse diseases. This review outlines how aberrant circular RNA biogenesis, subcellular location, and degradation are linked to disease progression, focusing on metaflammation and cancers. We also discuss potential therapeutic strategies and obstacles in targeting such disease-related circular RNAs.
RESUMEN
Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8+ T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8+ T cells from the cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8+ T cell immunosenescence drives leptomeningeal metastasis.
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Neoplasias Meníngeas , Animales , Ratones , Neoplasias Meníngeas/secundario , Neoplasias Meníngeas/terapia , Integrina alfa4beta1 , Linfocitos T CD8-positivosRESUMEN
The leukocyte Fcγ receptor (FcγR)-mediated response is important for the efficacy of therapeutic antibodies; however, little is known about the role of FcγRs in other cell types. Here we identify a subset of fibroblasts in human breast cancer that express CD16 (FcγRIII). An abundance of these cells in HER2+ breast cancer patients is associated with poor prognosis and response to trastuzumab. Functionally, upon trastuzumab stimulation, CD16+ fibroblasts reduce drug delivery by enhancing extracellular matrix stiffness. Interaction between trastuzumab and CD16 activates the intracellular SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway, leading to elevated contractile force and matrix production. Targeting of a Rho family guanine nucleotide exchange factor, VAV2, which is indispensable for the function of CD16 in fibroblasts rather than leukocytes, reverses desmoplasia provoked by CD16+ fibroblasts. Collectively, our study reveals a role for the fibroblast FcγR in drug resistance, and suggests that VAV2 is an attractive target to augment the effects of antibody treatments.
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Neoplasias de la Mama , Receptores de IgG , Humanos , Femenino , Trastuzumab/farmacología , Receptores de IgG/metabolismo , Fibroblastos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Matriz Extracelular/metabolismo , Receptor ErbB-2/metabolismo , Microambiente Tumoral , Proteínas Proto-Oncogénicas c-vav/genética , Proteínas Proto-Oncogénicas c-vav/metabolismoAsunto(s)
Interferón Tipo I , Neoplasias , Humanos , Inmunoterapia , Neoplasias/tratamiento farmacológicoRESUMEN
In the later-line setting or for patients with PD-L1-negative tumors, immunotherapy-based regimens remain ineffective against advanced triple-negative breast cancer (TNBC). In this multicentered phase II trial (NCT04303741), 46 patients with pretreated advanced TNBC were enrolled to receive camrelizumab 200 mg (day 1), and apatinib 250 mg daily, plus eribulin 1.4 mg/m2 (day 1 and 8) on a 21-day cycle until progression, or unacceptable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included toxicities, disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), and 1-year overall survival. With a median of 3 lines of prior chemotherapy in the advanced setting, 17.4% had received PD-1/PD-L1 blockade plus chemotherapy for advanced disease. The ORR was 37.0% (17/46, 95% CI 23.2-52.5). The DCR was 87.0% (40/46, 95% CI 73.7-95.1). Median PFS was 8.1 (95% CI 4.6-10.3) months. Tertiary lymphoid structure was associated with higher ORR. Patients with lower tumor PML or PLOD3 expression had favorable ORR and PFS. PD-L1 status was not associated with ORR/PFS. Grade 3/4 treatment-related adverse events occurred in 19 (41.3%) of 46 patients. Camrelizumab plus apatinib and eribulin shows promising efficacy with a measurable safety profile in patients with heavily pretreated advanced TNBC.
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Neoplasias de la Mama Triple Negativas , Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Furanos , Humanos , Cetonas , Piridinas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott-Aldrich syndrome protein (WASP)-Wiskott-Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.
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Citofagocitosis , Neoplasias , Proteínas del Citoesqueleto/metabolismo , Glutamina/farmacología , Humanos , Macrófagos , Dinámicas Mitocondriales , Neoplasias/tratamiento farmacológico , Fagocitosis , Proteína Quinasa C-theta/metabolismo , Proteína del Síndrome de Wiskott-Aldrich/metabolismoRESUMEN
The changes associated with malignancy are not only in cancer cells but also in environment in which cancer cells live. Metabolic reprogramming supports tumor cell high demand of biogenesis for their rapid proliferation, and helps tumor cell to survive under certain genetic or environmental stresses. Emerging evidence suggests that metabolic alteration is ultimately and tightly associated with genetic changes, in particular the dysregulation of key oncogenic and tumor suppressive signaling pathways. Cancer cells activate HIF signaling even in the presence of oxygen and in the absence of growth factor stimulation. This cancer metabolic phenotype, described firstly by German physiologist Otto Warburg, insures enhanced glycolytic metabolism for the biosynthesis of macromolecules. The conception of metabolite signaling, i.e., metabolites are regulators of cell signaling, provides novel insights into how reactive oxygen species (ROS) and other metabolites deregulation may regulate redox homeostasis, epigenetics, and proliferation of cancer cells. Moreover, the unveiling of noncanonical functions of metabolic enzymes, such as the moonlighting functions of phosphoglycerate kinase 1 (PGK1), reassures the importance of metabolism in cancer development. The metabolic, microRNAs, and ncRNAs alterations in cancer cells can be sorted and delivered either to intercellular matrix or to cancer adjacent cells to shape cancer microenvironment via media such as exosome. Among them, cancer microenvironmental cells are immune cells which exert profound effects on cancer cells. Understanding of all these processes is a prerequisite for the development of a more effective strategy to contain cancers.
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Neoplasias/metabolismo , Microambiente Tumoral , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/metabolismo , Progresión de la Enfermedad , Epigénesis Genética , Exosomas/genética , Exosomas/metabolismo , Humanos , Neoplasias/inmunología , Neoplasias/patología , Oncogenes/genética , Oxidación-Reducción , Fosfoglicerato Quinasa/genética , Fosfoglicerato Quinasa/metabolismo , ARN no Traducido/genética , ARN no Traducido/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Efecto Warburg en OncologíaRESUMEN
Eosinophilic inflammation is a feature of allergic asthma. Despite mounting evidence showing that chromatin filaments released from neutrophils mediate various diseases, the understanding of extracellular DNA from eosinophils is limited. Here we show that eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid are associated with the severity of asthma in patients. Functionally, we find that EETs augment goblet-cell hyperplasia, mucus production, infiltration of inflammatory cells and expressions of type 2 cytokines in experimental non-infection-related asthma using both pharmaceutical and genetic approaches. Multiple clinically relevant allergens trigger EET formation at least partially via thymic stromal lymphopoietin in vivo. Mechanically, EETs activate pulmonary neuroendocrine cells via the CCDC25-ILK-PKCα-CRTC1 pathway, which is potentiated by eosinophil peroxidase. Subsequently, the pulmonary neuroendocrine cells amplify allergic immune responses via neuropeptides and neurotransmitters. Therapeutically, inhibition of CCDC25 alleviates allergic inflammation. Together, our findings demonstrate a previously unknown role of EETs in integrating immunological and neurological cues to drive asthma progression.
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Asma/patología , Líquido del Lavado Bronquioalveolar/inmunología , Eosinófilos/patología , Trampas Extracelulares/fisiología , Inflamación/patología , Pulmón/patología , Células Neuroendocrinas/patología , Adulto , Animales , Asma/etiología , Asma/metabolismo , Estudios de Casos y Controles , Eosinófilos/inmunología , Eosinófilos/metabolismo , Femenino , Humanos , Inflamación/etiología , Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Neuroendocrinas/inmunología , Células Neuroendocrinas/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/patología , Proteína Quinasa C-alfa/genética , Proteína Quinasa C-alfa/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate-limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.
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Neoplasias de la Mama/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Histonas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Metabolismo de los Lípidos/genética , Células Madre Neoplásicas/metabolismo , Neprilisina/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Neoplasias de la Mama/genética , China , Femenino , Histonas/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Neprilisina/genética , Transducción de Señal/genética , Estearoil-CoA Desaturasa/genética , Microambiente Tumoral/genéticaRESUMEN
Reduced infiltration of anti-tumor lymphocytes remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that upregulation of regulator of G protein signaling (RGS)1 in helper TH1 cells and cytotoxic T lymphocytes (CTLs) reduced their trafficking to and survival in tumors and was associated with shorter survival of patients with breast and lung cancer. RGS1 was upregulated by type II interferon (IFN)-signal transducer and activator of transcription (STAT)1 signaling and impaired trafficking of circulating T cells to tumors by inhibiting calcium influx and suppressing activation of the kinases ERK and AKT. RGS1 knockdown in adoptively transferred tumor-specific CTLs significantly increased their infiltration and survival in breast and lung tumor grafts and effectively inhibited tumor growth in vivo, which was further improved when combined with programmed death ligand (PD-L)1 checkpoint inhibition. Our findings reveal RGS1 is important for tumor immune evasion and suggest that targeting RGS1 may provide a new strategy for tumor immunotherapy.
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Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Quimiotaxis de Leucocito , Linfocitos Infiltrantes de Tumor/metabolismo , Proteínas RGS/metabolismo , Subgrupos de Linfocitos T/metabolismo , Animales , Apoptosis , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/inmunología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , Línea Celular Tumoral , Quimiocinas/metabolismo , Técnicas de Cocultivo , Citotoxicidad Inmunológica , Femenino , Humanos , Inmunoterapia Adoptiva , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplante , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microscopía Fluorescente , Microscopía por Video , Proteínas RGS/genética , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Factores de Tiempo , Imagen de Lapso de Tiempo , Células Tumorales Cultivadas , Escape del TumorRESUMEN
Mitochondrial noncoding RNAs (mt-ncRNAs) include noncoding RNAs inside the mitochondria that are transcribed from the mitochondrial genome or nuclear genome, and noncoding RNAs transcribed from the mitochondrial genome that are transported to the cytosol or nucleus. Recent findings have revealed that mt-ncRNAs play important roles in not only mitochondrial functions, but also other cellular activities. This review proposes a classification of mt-ncRNAs and outlines the emerging understanding of mitochondrial circular RNAs (mt-circRNAs), mitochondrial microRNAs (mitomiRs), and mitochondrial long noncoding RNAs (mt-lncRNAs), with an emphasis on their identification and functions.
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Mitocondrias/genética , ARN no Traducido/genética , Animales , Epigénesis Genética , Regulación de la Expresión Génica , Humanos , ARN Mitocondrial/genética , ARN no Traducido/clasificaciónRESUMEN
Notch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Receptor Notch1/genética , Proteína de Replicación C/genética , Transducción de Señal/genética , Células A549 , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Retroalimentación Fisiológica , Femenino , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Metástasis de la Neoplasia , Receptor Notch1/metabolismo , Proteína de Replicación C/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Targeted regulation of mitochondrial gene expression is challenging due to the lack of a mitochondria-specific delivery system. We have previously developed various stimuli-responsive nanoparticle (NP)-based delivery systems to transport nucleic acids for regulation of target gene expression. This protocol describes the design and preparation of an NP platform for mitochondria-specific gene delivery (mito-NP). We use mito-NP in primary liver fibroblasts that are transplanted into mice. Mito-NP can be used to deliver various nucleic acid therapeutics and to treat mitochondria-regulated diseases. For complete details on the use and execution of this protocol, please refer to Zhao et al. (2020).