RESUMEN
Breast cancer remains a leading cause of cancer-related mortality in women, reflecting profound disease heterogeneity, metastasis, and therapeutic resistance. Over the last decade, genomic and transcriptomic data have been integrated on an unprecedented scale and revealed distinct cancer subtypes, critical molecular drivers, clonal evolutionary trajectories, and prognostic signatures. Furthermore, multi-dimensional integration of high-resolution single-cell and spatial technologies has highlighted the importance of the entire breast cancer ecosystem and the presence of distinct cellular "neighborhoods." Clinically, a plethora of new targeted therapies has emerged, now being rapidly incorporated into routine care. Resistance to therapy, however, remains a crucial challenge for the field.
Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Perfilación de la Expresión Génica , Genómica , Transcriptoma , Resistencia a AntineoplásicosRESUMEN
Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3-31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2-16 years later show that many primary DCIS had already undergone whole-genome doubling and clonal diversification and that they shared genomic lineages with persistent subclones in the recurrences. Evolutionary analysis suggests that most DCIS cases in our cohort underwent an evolutionary bottleneck, and further identified chromosome aberrations in the persistent subclones that were associated with recurrence.
Asunto(s)
Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal no Infiltrante , Femenino , Humanos , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Progresión de la Enfermedad , Genómica/métodos , Análisis de Expresión Génica de una Sola Célula , Línea Celular TumoralRESUMEN
Tumors contain bacteria, but the functional significance of this tumor microbiota is not appreciated. Fu et al. show that bacteria within breast tumor cells contribute to metastasis, in part, by enhancing tumor cell survival to mechanical fluid shear stress as would be found in the circulation.
Asunto(s)
Bacterias , Neoplasias de la Mama , Metástasis de la Neoplasia , Neoplasias de la Mama/microbiología , Neoplasias de la Mama/patología , Supervivencia Celular , Femenino , Humanos , Estrés MecánicoRESUMEN
Tumor-resident intracellular microbiota is an emerging tumor component that has been documented for a variety of cancer types with unclear biological functions. Here, we explored the functional significance of these intratumor bacteria, primarily using a murine spontaneous breast-tumor model MMTV-PyMT. We found that depletion of intratumor bacteria significantly reduced lung metastasis without affecting primary tumor growth. During metastatic colonization, intratumor bacteria carried by circulating tumor cells promoted host-cell survival by enhancing resistance to fluid shear stress by reorganizing actin cytoskeleton. We further showed that intratumor administration of selected bacteria strains isolated from tumor-resident microbiota promoted metastasis in two murine tumor models with significantly different levels of metastasis potential. Our findings suggest that tumor-resident microbiota, albeit at low biomass, play an important role in promoting cancer metastasis, intervention of which might therefore be worth exploring for advancing oncology care.
Asunto(s)
Neoplasias de la Mama , Microbiota , Metástasis de la Neoplasia , Animales , Neoplasias de la Mama/microbiología , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones , Células Neoplásicas Circulantes/patologíaRESUMEN
Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Diferenciación Celular , Estudios de Cohortes , Progresión de la Enfermedad , Células Epiteliales/patología , Epitelio/patología , Matriz Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Fenotipo , Análisis de la Célula Individual , Células del Estroma/patología , Microambiente TumoralRESUMEN
Mary-Claire King's approach to genetics has had a major impact on breast and ovarian cancer and, more recently, mental illnesses including schizophrenia. Science writer Kendall Morgan talked with Mary-Claire, recipient of a 2021 Canada Gairdner International Award, about her life, her lengthy quest to discover the genetic basis of susceptibility to breast cancer, the struggles for women in science, and much more. An edited version of this conversation is presented below.
Asunto(s)
Neoplasias de la Mama/patología , Neoplasias Ováricas/patología , Distinciones y Premios , Neoplasias de la Mama/genética , Femenino , Genética , Humanos , Trastornos Mentales/genética , Trastornos Mentales/patología , Neoplasias Ováricas/genética , Esquizofrenia/genética , Esquizofrenia/patologíaRESUMEN
Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.
Asunto(s)
Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Daño del ADN , Exodesoxirribonucleasas/metabolismo , Membrana Nuclear/metabolismo , Fosfoproteínas/metabolismo , Animales , Línea Celular , Senescencia Celular , Colágeno/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Invasividad Neoplásica , Membrana Nuclear/ultraestructura , Proteolisis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Microambiente Tumoral , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Secuencia de Bases , Neoplasias de la Mama/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/química , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genómica , Humanos , Ratones Endogámicos NOD , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Oncogenes , Unión Proteica/efectos de los fármacos , Dominios Proteicos , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Tamoxifeno/farmacología , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Ras GTPase-activating protein-binding proteins 1 and 2 (G3BP1 and G3BP2, respectively) are widely recognized as core components of stress granules (SGs). We report that G3BPs reside at the cytoplasmic surface of lysosomes. They act in a non-redundant manner to anchor the tuberous sclerosis complex (TSC) protein complex to lysosomes and suppress activation of the metabolic master regulator mechanistic target of rapamycin complex 1 (mTORC1) by amino acids and insulin. Like the TSC complex, G3BP1 deficiency elicits phenotypes related to mTORC1 hyperactivity. In the context of tumors, low G3BP1 levels enhance mTORC1-driven breast cancer cell motility and correlate with adverse outcomes in patients. Furthermore, G3bp1 inhibition in zebrafish disturbs neuronal development and function, leading to white matter heterotopia and neuronal hyperactivity. Thus, G3BPs are not only core components of SGs but also a key element of lysosomal TSC-mTORC1 signaling.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , ADN Helicasas/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Esclerosis Tuberosa/metabolismo , Secuencia de Aminoácidos , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Gránulos Citoplasmáticos/efectos de los fármacos , Gránulos Citoplasmáticos/metabolismo , ADN Helicasas/química , Evolución Molecular , Femenino , Humanos , Insulina/farmacología , Proteínas de Membrana de los Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fenotipo , Proteínas de Unión a Poli-ADP-Ribosa/química , ARN Helicasas/química , Proteínas con Motivos de Reconocimiento de ARN/química , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Pez Cebra/metabolismoRESUMEN
The integration of mass spectrometry-based proteomics with next-generation DNA and RNA sequencing profiles tumors more comprehensively. Here this "proteogenomics" approach was applied to 122 treatment-naive primary breast cancers accrued to preserve post-translational modifications, including protein phosphorylation and acetylation. Proteogenomics challenged standard breast cancer diagnoses, provided detailed analysis of the ERBB2 amplicon, defined tumor subsets that could benefit from immune checkpoint therapy, and allowed more accurate assessment of Rb status for prediction of CDK4/6 inhibitor responsiveness. Phosphoproteomics profiles uncovered novel associations between tumor suppressor loss and targetable kinases. Acetylproteome analysis highlighted acetylation on key nuclear proteins involved in the DNA damage response and revealed cross-talk between cytoplasmic and mitochondrial acetylation and metabolism. Our results underscore the potential of proteogenomics for clinical investigation of breast cancer through more accurate annotation of targetable pathways and biological features of this remarkably heterogeneous malignancy.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinogénesis/genética , Carcinogénesis/patología , Terapia Molecular Dirigida , Proteogenómica , Desaminasas APOBEC/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Estudios de Cohortes , Daño del ADN , Reparación del ADN , Femenino , Humanos , Inmunoterapia , Metabolómica , Persona de Mediana Edad , Mutagénesis/genética , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Receptor ErbB-2/metabolismo , Proteína de Retinoblastoma/metabolismo , Microambiente Tumoral/inmunologíaRESUMEN
Cancer therapies kill tumors either directly or indirectly by evoking immune responses and have been combined with varying levels of success. Here, we describe a paradigm to control cancer growth that is based on both direct tumor killing and the triggering of protective immunity. Genetic ablation of serine protease inhibitor SerpinB9 (Sb9) results in the death of tumor cells in a granzyme B (GrB)-dependent manner. Sb9-deficient mice exhibited protective T cell-based host immunity to tumors in association with a decline in GrB-expressing immunosuppressive cells within the tumor microenvironment (TME). Maximal protection against tumor development was observed when the tumor and host were deficient in Sb9. The therapeutic utility of Sb9 inhibition was demonstrated by the control of tumor growth, resulting in increased survival times in mice. Our studies describe a molecular target that permits a combination of tumor ablation, interference within the TME, and immunotherapy in one potential modality.
Asunto(s)
Citotoxicidad Inmunológica , Inmunoterapia , Proteínas de la Membrana/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Serpinas/metabolismo , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Progresión de la Enfermedad , Femenino , Eliminación de Gen , Granzimas/metabolismo , Inmunidad/efectos de los fármacos , Melanoma/patología , Ratones Endogámicos C57BL , Neoplasias/prevención & control , Bibliotecas de Moléculas Pequeñas/farmacología , Células del Estroma/efectos de los fármacos , Células del Estroma/patología , Microambiente Tumoral/efectos de los fármacosRESUMEN
Mutations in the BRCA1 and BRCA2 genes predispose afflicted individuals to breast, ovarian, and other cancers. The BRCA-encoded products form complexes with other tumor suppressor proteins and with the recombinase enzyme RAD51 to mediate chromosome damage repair by homologous recombination and also to protect stressed DNA replication forks against spurious nucleolytic attrition. Understanding how the BRCA tumor suppressor network executes its biological functions would provide the foundation for developing targeted cancer therapeutics, but progress in this area has been greatly hampered by the challenge of obtaining purified BRCA complexes for mechanistic studies. In this article, we review how recent effort begins to overcome this technical challenge, leading to functional and structural insights into the biochemical attributes of these complexes and the multifaceted roles that they fulfill in genome maintenance. We also highlight the major mechanistic questions that remain.
Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Redes Reguladoras de Genes , Recombinasa Rad51/genética , Reparación del ADN por Recombinación , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Proteína BRCA1/química , Proteína BRCA1/metabolismo , Proteína BRCA2/química , Proteína BRCA2/metabolismo , Sitios de Unión , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , ADN/química , ADN/genética , ADN/metabolismo , Roturas del ADN de Doble Cadena , Replicación del ADN , Femenino , Genoma Humano , Inestabilidad Genómica , Humanos , Modelos Moleculares , Unión Proteica , Estructura Secundaria de Proteína , Recombinasa Rad51/química , Recombinasa Rad51/metabolismo , Proteínas Supresoras de Tumor/química , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I â KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy.
Asunto(s)
Neoplasias de la Mama , Epigénesis Genética , Histona Demetilasas , Interferón Tipo I , Antraciclinas/metabolismo , Antraciclinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Histona Demetilasas/metabolismo , Humanos , Interferón Tipo I/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
Loss of BRCA1 p220 function often results in basal-like breast cancer (BLBC), but the underlying disease mechanism is largely opaque. In mammary epithelial cells (MECs), BRCA1 interacts with multiple proteins, including NUMB and HES1, to form complexes that participate in interstrand crosslink (ICL) DNA repair and MEC differentiation control. Unrepaired ICL damage results in aberrant transdifferentiation to a mesenchymal state of cultured, human basal-like MECs and to a basal/mesenchymal state in primary mouse luminal MECs. Loss of BRCA1, NUMB, or HES1 or chemically induced ICL damage in primary murine luminal MECs results in persistent DNA damage that triggers luminal to basal/mesenchymal transdifferentiation. In vivo single-cell analysis revealed a time-dependent evolution from normal luminal MECs to luminal progenitor-like tumor cells with basal/mesenchymal transdifferentiation during murine BRCA1 BLBC development. Growing DNA damage accompanied this malignant transformation.
Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Transdiferenciación Celular/genética , Daño del ADN/genética , Reparación del ADN/genética , Glándulas Mamarias Animales/patología , Animales , Proteína BRCA1/metabolismo , Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/patología , Diferenciación Celular/genética , Transformación Celular Neoplásica , Modelos Animales de Enfermedad , Células Epiteliales/metabolismo , Femenino , Células HEK293 , Humanos , Células MCF-7 , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Factor de Transcripción HES-1/metabolismo , TransfecciónRESUMEN
Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor cell composition, including phenotypic abnormalities and phenotype dominance. Relationship analyses between tumor and immune cells revealed characteristics of ecosystems related to immunosuppression and poor prognosis. High frequencies of PD-L1+ tumor-associated macrophages and exhausted T cells were found in high-grade ER+ and ER- tumors. This large-scale, single-cell atlas deepens our understanding of breast tumor ecosystems and suggests that ecosystem-based patient classification will facilitate identification of individuals for precision medicine approaches targeting the tumor and its immunoenvironment.
Asunto(s)
Neoplasias de la Mama , Tolerancia Inmunológica , Linfocitos Infiltrantes de Tumor , Macrófagos , Microambiente Tumoral/inmunología , Antígeno B7-H1/inmunología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Macrófagos/inmunología , Macrófagos/patología , Proteínas de Neoplasias/inmunología , Tasa de SupervivenciaRESUMEN
The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.
Asunto(s)
Neoplasias de la Mama/genética , Metástasis de la Neoplasia/genética , Células Neoplásicas Circulantes/patología , Animales , Neoplasias de la Mama/patología , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Metilación de ADN/fisiología , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Proteína Homeótica Nanog/metabolismo , Metástasis de la Neoplasia/fisiopatología , Células Neoplásicas Circulantes/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción SOXB1/metabolismo , Complejo Correpresor Histona Desacetilasa y Sin3RESUMEN
CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.
Asunto(s)
Linfocitos T CD8-positivos/metabolismo , ARN Helicasas/genética , Animales , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Citocinas/genética , Citocinas/metabolismo , Femenino , Humanos , Memoria Inmunológica , Inmunoterapia , Masculino , Ratones , Ratones Noqueados , FN-kappa B/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , ARN Helicasas/deficiencia , ARN Guía de Kinetoplastida/metabolismo , TranscriptomaRESUMEN
Accurate prediction of long-term outcomes remains a challenge in the care of cancer patients. Due to the difficulty of serial tumor sampling, previous prediction tools have focused on pretreatment factors. However, emerging non-invasive diagnostics have increased opportunities for serial tumor assessments. We describe the Continuous Individualized Risk Index (CIRI), a method to dynamically determine outcome probabilities for individual patients utilizing risk predictors acquired over time. Similar to "win probability" models in other fields, CIRI provides a real-time probability by integrating risk assessments throughout a patient's course. Applying CIRI to patients with diffuse large B cell lymphoma, we demonstrate improved outcome prediction compared to conventional risk models. We demonstrate CIRI's broader utility in analogous models of chronic lymphocytic leukemia and breast adenocarcinoma and perform a proof-of-concept analysis demonstrating how CIRI could be used to develop predictive biomarkers for therapy selection. We envision that dynamic risk assessment will facilitate personalized medicine and enable innovative therapeutic paradigms.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Linfoma de Células B Grandes Difuso/patología , Medicina de Precisión , Algoritmos , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , ADN Tumoral Circulante/sangre , Femenino , Humanos , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Terapia Neoadyuvante , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Medición de Riesgo , Resultado del TratamientoRESUMEN
Estrogen receptor-positive (ER+) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER "degraders" exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.