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1.
Cell ; 184(2): 384-403.e21, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33450205

RESUMO

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.


Assuntos
Antivirais/farmacologia , Imunidade/efeitos dos fármacos , Spliceossomos/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Feminino , Amplificação de Genes/efeitos dos fármacos , Humanos , Íntrons/genética , Camundongos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Splicing de RNA/efeitos dos fármacos , Splicing de RNA/genética , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais/efeitos dos fármacos , Spliceossomos/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/genética
2.
Cancer Metastasis Rev ; 35(4): 601-629, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27858305

RESUMO

Human cancers exhibit formidable molecular heterogeneity, to a large extent accounting for the incomplete and transitory efficacy of current anti-cancer therapies. However, neoplastic cells alone do not manifest the disease, but conscript a battery of non-tumor cells to enable and sustain hallmark capabilities of cancer. Escaping immunosurveillance is one of such capabilities. Tumors evolve immunosuppressive microenvironment to subvert anti-tumor immunity. In this review, we will focus on tumor-associated myeloid cells, which constitute an essential part of the immune microenvironment and reciprocally interact with cancer cells to establish malignancy toward metastasis. The diversity and plasticity of these cells constitute another layer of heterogeneity, beyond the heterogeneity of cancer cells themselves. We envision that immune microenvironment co-evolves with the genetic heterogeneity of tumor. Addressing the question of how genetically distinct tumors shape and are shaped by unique immune microenvironment will provide an attractive rationale to develop novel immunotherapeutic modalities. Here, we discuss the complex nature of tumor microenvironment, with an emphasis on the cellular and functional heterogeneity among tumor-associated myeloid cells as well as immune environment heterogeneity in the context of a full spectrum of human breast cancers.


Assuntos
Neoplasias/genética , Neoplasias/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Animais , Progressão da Doença , Heterogeneidade Genética , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Neoplasias/irrigação sanguínea , Neoplasias/patologia
3.
Dev Cell ; 56(8): 1100-1117.e9, 2021 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-33878299

RESUMO

Estrogen receptor-positive (ER+) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.


Assuntos
Adaptação Fisiológica , Osso e Ossos/patologia , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Microambiente Tumoral , Animais , Neoplasias Ósseas/secundário , Neoplasias da Mama/metabolismo , Comunicação Celular , Evolução Clonal , Modelos Animais de Doenças , Regulação para Baixo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Junções Comunicantes/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Humanos , Células MCF-7 , Camundongos , Micrometástase de Neoplasia , Osteogênese , Transdução de Sinais
4.
Nat Cancer ; 1(7): 709-722, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-35122036

RESUMO

Polyclonal metastases frequently arise from clusters of circulating tumor cells (CTCs). CTC clusters metastasize better than single CTCs, but the underlying molecular mechanisms are poorly understood. Here, we show that polyclonal metastatic seeds exhibit higher resistance to natural killer (NK) cell killing. Using breast cancer models, we observed higher proportions of polyclonal lung metastasis in immunocompetent mice compared with mice lacking NK cells. Depleting NK cells selectively increased monoclonal but not polyclonal metastases, suggesting that CTC clusters are less sensitive to NK-mediated suppression. Transcriptional analyses revealed that clusters have elevated expression of cell-cell adhesion and epithelial genes, which is associated with decreased expression of NK cell activating ligands. Furthermore, perturbing tumor cell epithelial status altered NK ligand expression and sensitivity to NK-mediated killing. Collectively, our findings show that NK cells can determine the fate of CTCs of different epithelial and mesenchymal states, and impact metastatic clonal evolution by favoring polyclonal seeding.


Assuntos
Neoplasias Pulmonares , Células Neoplásicas Circulantes , Animais , Contagem de Células , Células Matadoras Naturais , Neoplasias Pulmonares/metabolismo , Camundongos , Monitorização Imunológica
5.
JCI Insight ; 52019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31265437

RESUMO

Hormones produced by the anterior pituitary gland regulate an array of important physiological functions, but pituitary hormone disorders are not fully understood. Herein we report that genetically-engineered mice with deletion of the hedgehog signaling receptor Patched1 by S100a4 promoter-driven Cre recombinase (S100a4-Cre;Ptch1fl/fl mutants) exhibit adult-onset hypogonadotropic hypogonadism and multiple pituitary hormone disorders. During the transition from puberty to adult, S100a4-Cre;Ptch1fl/fl mice of both sexes develop hypogonadism coupled with reduced gonadotropin levels. Their pituitary glands also display severe structural and functional abnormalities, as revealed by transmission electron microscopy and expression of key genes regulating pituitary endocrine functions. S100a4-Cre activity in the anterior pituitary gland is restricted to CD45+ cells of hematopoietic origin, including folliculo-stellate cells and other immune cell types, causing sex-specific changes in the expression of genes regulating the local microenvironment of the anterior pituitary. These findings provide in vivo evidence for the importance of pituitary hematopoietic cells in regulating fertility and endocrine function, in particular during sexual maturation and likely through sexually dimorphic mechanisms. These findings support a previously unrecognized role of hematopoietic cells in causing hypogonadotropic hypogonadism and provide inroads into the molecular and cellular basis for pituitary hormone disorders in humans.


Assuntos
Hipogonadismo/metabolismo , Integrases/metabolismo , Receptor Patched-1/metabolismo , Hipófise/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Animais , Epididimo/patologia , Feminino , Humanos , Hipogonadismo/genética , Hipogonadismo/patologia , Masculino , Camundongos , Camundongos Knockout , Ovário/patologia , Receptor Patched-1/genética , Adeno-Hipófise/metabolismo , Reprodução/fisiologia , Glândulas Seminais/patologia , Maturidade Sexual , Transdução de Sinais , Testículo , Testosterona/sangue , Útero/patologia
6.
Nat Cell Biol ; 21(9): 1113-1126, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451770

RESUMO

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.


Assuntos
Imunoterapia , Células Mieloides/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Microambiente Tumoral/imunologia , Animais , Modelos Animais de Doenças , Feminino , Granulócitos/imunologia , Imunoterapia/métodos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Neoplasias de Mama Triplo Negativas/patologia
7.
Nat Cell Biol ; 18(6): 632-44, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27183469

RESUMO

Myeloid-derived suppressor cells (MDSCs) play critical roles in primary and metastatic cancer progression. MDSC regulation is widely variable even among patients harbouring the same type of malignancy, and the mechanisms governing such heterogeneity are largely unknown. Here, integrating human tumour genomics and syngeneic mammary tumour models, we demonstrate that mTOR signalling in cancer cells dictates a mammary tumour's ability to stimulate MDSC accumulation through regulating G-CSF. Inhibiting this pathway or its activators (for example, FGFR) impairs tumour progression, which is partially rescued by restoring MDSCs or G-CSF. Tumour-initiating cells (TICs) exhibit elevated G-CSF. MDSCs reciprocally increase TIC frequency through activating Notch in tumour cells, forming a feedforward loop. Analyses of primary breast cancers and patient-derived xenografts corroborate these mechanisms in patients. These findings establish a non-canonical oncogenic role of mTOR signalling in recruiting pro-tumorigenic MDSCs and show how defined cancer subsets may evolve to promote and depend on a distinct immune microenvironment.


Assuntos
Transformação Celular Neoplásica/genética , Células Supressoras Mieloides/citologia , Serina-Treonina Quinases TOR/genética , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Camundongos , Microambiente Tumoral/genética
8.
Int J Oncol ; 42(5): 1807-14, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23545901

RESUMO

In the present study, the expression of human γ-aminobutyrate type A (GABAA) receptor-binding protein (GABARBP) is downregulated in ovarian cancer cell lines and tissues. We also found that the specific function of GABAPBP was that of a novel pro-apoptotic protein. Both GABARBP and cisplatin suppressed cancer cell proliferation in a concentration-dependent manner. The combined treatment of GABARBP and cisplatin was more effective in inhibiting cell growth, as well as cell migration, than with either drug treatment alone. At the same time, the treatment combination is correlated with the downregulation of cyclin D1 and CDK4, arrested cell cycle progression in the G0-G1 phase and enhancing p53 expression, while also reducing Bcl-2 and Bcl-xL expression. The p53 and p21 promoter luciferase activities were induced by GABARBP, whereas there was no effect on the p53-/- and p21-/- system. In addition, p53 activity was validated with UV irradiation and siGABARBP. Taken together, our results indicate that GABARBP can regulate the pro-apoptotic activity of cisplatin via the upregulation of p53 expression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Apoptose/genética , Proteínas Reguladoras de Apoptose , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Associadas aos Microtúbulos/biossíntese , Neoplasias/tratamento farmacológico , Neoplasias/patologia
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