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Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit anti-tumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multi-polar spindles, and chromosomal instability (CIN). Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated CIN for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of TNBC patients treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.
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Breast cancer subtypes and their phenotypes parallel different stages of the mammary epithelial cell developmental hierarchy. Discovering mechanisms that control lineage identity could provide novel avenues for mitigating disease progression. Here we report that the transcriptional corepressor TLE3 is a guardian of luminal cell fate in breast cancer and operates independently of the estrogen receptor. In luminal breast cancer, TLE3 actively repressed the gene-expression signature associated with highly aggressive basal-like breast cancers (BLBC). Moreover, maintenance of the luminal lineage depended on the appropriate localization of TLE3 to its transcriptional targets, a process mediated by interactions with FOXA1. By repressing genes that drive BLBC phenotypes, including SOX9 and TGFß2, TLE3 prevented the acquisition of a hybrid epithelial-mesenchymal state and reduced metastatic capacity and aggressive cellular behaviors. These results establish TLE3 as an essential transcriptional repressor that sustains the more differentiated and less metastatic nature of luminal breast cancers. Approaches to induce TLE3 expression could promote the acquisition of less aggressive, more treatable disease states to extend patient survival. SIGNIFICANCE: Transcriptional corepressor TLE3 actively suppresses SOX9 and TGFß transcriptional programs to sustain the luminal lineage identity of breast cancer cells and to inhibit metastatic progression.
Assuntos
Neoplasias , Fatores de Transcrição , Diferenciação Celular , Proteínas Correpressoras/genética , Receptores de Estrogênio/metabolismo , Fator de Crescimento Transformador beta , Neoplasias da Mama/metabolismo , HumanosRESUMO
BACKGROUND & AIMS: Mechanisms contributing to the onset and progression of Barrett's (BE)-associated esophageal adenocarcinoma (EAC) remain elusive. Here, we interrogated the major signaling pathways deregulated early in the development of Barrett's neoplasia. METHODS: Whole-transcriptome RNA sequencing analysis was performed in primary BE, EAC, normal esophageal squamous, and gastric biopsy tissues (n = 89). Select pathway components were confirmed by quantitative polymerase chain reaction in an independent cohort of premalignant and malignant biopsy tissues (n = 885). Functional impact of selected pathway was interrogated using transcriptomic, proteomic, and pharmacogenetic analyses in mammalian esophageal organotypic and patient-derived BE/EAC cell line models, in vitro and/or in vivo. RESULTS: The vast majority of primary BE/EAC tissues and cell line models showed hyperactivation of EphB2 signaling. Transcriptomic/proteomic analyses identified EphB2 as an endogenous binding partner of MYC binding protein 2, and an upstream regulator of c-MYC. Knockdown of EphB2 significantly impeded the viability/proliferation of EAC and BE cells in vitro/in vivo. Activation of EphB2 in normal esophageal squamous 3-dimensional organotypes disrupted epithelial maturation and promoted columnar differentiation programs, notably including MYC. EphB2 and MYC showed selective induction in esophageal submucosal glands with acinar ductal metaplasia, and in a porcine model of BE-like esophageal submucosal gland spheroids. Clinically approved inhibitors of MEK, a protein kinase that regulates MYC, effectively suppressed EAC tumor growth in vivo. CONCLUSIONS: The EphB2 signaling is frequently hyperactivated across the BE-EAC continuum. EphB2 is an upstream regulator of MYC, and activation of EphB2-MYC axis likely precedes BE development. Targeting EphB2/MYC could be a promising therapeutic strategy for this often refractory and aggressive cancer.
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Esôfago de Barrett , Carcinoma de Células Escamosas , Neoplasias Esofágicas , Suínos , Animais , Esôfago de Barrett/patologia , Efrina-B2/genética , Proteômica , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/patologia , Proto-Oncogenes , Proteínas Tirosina Quinases/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mamíferos/genéticaRESUMO
Current tailored-therapy efforts in cancer are largely focused on a small number of highly recurrently mutated driver genes but therapeutic targeting of these oncogenes remains challenging. However, the vast number of genes mutated infrequently across cancers has received less attention, in part, due to a lack of understanding of their biological significance. We present SYSMut, an extendable systems biology platform that can robustly infer the biologic consequences of somatic mutations by integrating routine multiomics profiles in primary tumors. We establish SYSMut's improved performance vis-à-vis state-of-the-art driver gene identification methodologies by recapitulating the functional impact of known driver genes, while additionally identifying novel functionally impactful mutated genes across 29 cancers. Subsequent application of SYSMut on low-frequency gene mutations in head and neck squamous cell (HNSC) cancers, followed by molecular and pharmacogenetic validation, revealed the lipidogenic network as a novel therapeutic vulnerability in aggressive HNSC cancers. SYSMut is thus a robust scalable framework that enables the discovery of new targetable avenues in cancer.
Assuntos
Neoplasias , Humanos , Mutação , Neoplasias/genética , Oncogenes , Biologia de SistemasRESUMO
Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist, is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable trilineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects, including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2-proficient normal hematopoietic stem and progenitor cells, in part because of its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2 mutant-associated or TET deficiency-associated myeloid malignancies.
Assuntos
Anemia Aplástica , Benzoatos/farmacologia , Proliferação de Células , Proteínas de Ligação a DNA , Dioxigenases , Células-Tronco Hematopoéticas/enzimologia , Hidrazinas/farmacologia , Pirazóis/farmacologia , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Anemia Aplástica/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dioxigenases/antagonistas & inibidores , Dioxigenases/genética , Dioxigenases/metabolismo , Humanos , Camundongos , Camundongos KnockoutRESUMO
PURPOSE: VSIR is a novel immune checkpoint protein whose expression on tumor cells across cancers remains largely uncharacterized. Here we purposed to decode the pan-cancer biologic and clinical significance of VSIR overexpression in the tumor compartment. EXPERIMENTAL DESIGN: We performed multi-omics integrative analyses of 9,735 tumor samples to identify cancers with non-leukocytic expression of VSIR (VSIR High), followed by association with overall survival and immune cell infiltration levels. Orthogonal assessments of VSIR protein expression and lymphocytic infiltration were performed using quantitative immunofluorescence (QIF). RESULTS: Integrative modeling identified a subset of cancer types as being enriched for VSIR High tumors. VSIR High tumors were associated with significantly poorer overall survival in immunogenic ovarian serous adenocarcinoma (SA) and oral cavity squamous cell carcinoma (SCC). QIF assessments in an independent validation cohort confirmed overexpression of VSIR as being associated with poorer overall survival within immunogenic oral cavity SCC. VSIR overexpression was associated with lower CD4 helper T-cell infiltration in both ovarian SA and oral cavity SCC, but did not impact CD8 T-cell infiltration. VSIR overexpressing tumors in both cancer types exhibited significantly higher STAT3 signaling activity. Pharmacologic inhibition of STAT3 signaling resulted in dose-dependent reduction of VSIR expression in ovarian SA and oral cavity SCC cells. CONCLUSIONS: The STAT3-VSIR axis is a potentially significant immunomodulatory mechanism in oral cavity and ovarian cancers, whose activation is associated with poorer survival and an immune microenvironment marked by decreased CD4 helper T-cell activity. The role of VSIR as a tumor-intrinsic modulator of resistance to immunotherapy warrants further exploration.
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Carcinoma de Células Escamosas , Cistadenocarcinoma Seroso , Neoplasias de Cabeça e Pescoço , Linfócitos T CD8-Positivos , Neoplasias de Cabeça e Pescoço/genética , Humanos , Imunoterapia , Fator de Transcrição STAT3/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral/genéticaRESUMO
Circulating tumor cell (CTC) clusters mediate metastasis at a higher efficiency and are associated with lower overall survival in breast cancer compared to single cells. Combining single-cell RNA sequencing and protein analyses, here we report the profiles of primary tumor cells and lung metastases of triple-negative breast cancer (TNBC). ICAM1 expression increases by 200-fold in the lung metastases of three TNBC patient-derived xenografts (PDXs). Depletion of ICAM1 abrogates lung colonization of TNBC cells by inhibiting homotypic tumor cell-tumor cell cluster formation. Machine learning-based algorithms and mutagenesis analyses identify ICAM1 regions responsible for homophilic ICAM1-ICAM1 interactions, thereby directing homotypic tumor cell clustering, as well as heterotypic tumor-endothelial adhesion for trans-endothelial migration. Moreover, ICAM1 promotes metastasis by activating cellular pathways related to cell cycle and stemness. Finally, blocking ICAM1 interactions significantly inhibits CTC cluster formation, tumor cell transendothelial migration, and lung metastasis. Therefore, ICAM1 can serve as a novel therapeutic target for metastasis initiation of TNBC.
Assuntos
Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias Pulmonares/secundário , Células Neoplásicas Circulantes/patologia , Neoplasias de Mama Triplo Negativas/patologia , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Agregação Celular , Ciclo Celular , Transformação Celular Neoplásica , Humanos , Molécula 1 de Adesão Intercelular/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Células Neoplásicas Circulantes/metabolismo , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Migração Transendotelial e Transepitelial , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: Recent epidemiological studies have suggested that sexual dimorphism influences treatment response and prognostic outcome in glioblastoma (GBM). To this end, we sought to (i) identify distinct sex-specific radiomic phenotypes-from tumor subcompartments (peritumoral edema, enhancing tumor, and necrotic core) using pretreatment MRI scans-that are prognostic of overall survival (OS) in GBMs, and (ii) investigate radiogenomic associations of the MRI-based phenotypes with corresponding transcriptomic data, to identify the signaling pathways that drive sex-specific tumor biology and treatment response in GBM. METHODS: In a retrospective setting, 313 GBM patients (maleâ =â 196, femaleâ =â 117) were curated from multiple institutions for radiomic analysis, where 130 were used for training and independently validated on a cohort of 183 patients. For the radiogenomic analysis, 147 GBM patients (maleâ =â 94, femaleâ =â 53) were used, with 125 patients in training and 22 cases for independent validation. RESULTS: Cox regression models of radiomic features from gadolinium T1-weighted MRI allowed for developing more precise prognostic models, when trained separately on male and female cohorts. Our radiogenomic analysis revealed higher expression of Laws energy features that capture spots and ripple-like patterns (representative of increased heterogeneity) from the enhancing tumor region, as well as aggressive biological processes of cell adhesion and angiogenesis to be more enriched in the "high-risk" group of poor OS in the male population. In contrast, higher expressions of Laws energy features (which detect levels and edges) from the necrotic core with significant involvement of immune related signaling pathways was observed in the "low-risk" group of the female population. CONCLUSIONS: Sexually dimorphic radiogenomic models could help risk-stratify GBM patients for personalized treatment decisions.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
The phenotypes of each breast cancer subtype are defined by their transcriptomes. However, the transcription factors that regulate differential patterns of gene expression that contribute to specific disease outcomes are not well understood. Here, using gene silencing and overexpression approaches, RNA-Seq, and splicing analysis, we report that the transcription factor B-cell leukemia/lymphoma 11A (BCL11A) is highly expressed in triple-negative breast cancer (TNBC) and drives metastatic disease. Moreover, BCL11A promotes cancer cell invasion by suppressing the expression of muscleblind-like splicing regulator 1 (MBNL1), a splicing regulator that suppresses metastasis. This ultimately increases the levels of an alternatively spliced isoform of integrin-α6 (ITGA6), which is associated with worse patient outcomes. These results suggest that BCL11A sustains TNBC cell invasion and metastatic growth by repressing MBNL1-directed splicing of ITGA6 Our findings also indicate that BCL11A lies at the interface of transcription and splicing and promotes aggressive TNBC phenotypes.
Assuntos
Regulação Neoplásica da Expressão Gênica , Invasividade Neoplásica/genética , Proteínas Repressoras/genética , Neoplasias de Mama Triplo Negativas/genética , Regulação para Cima , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of NEK2 was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, in vitro. In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple in vivo models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. SIGNIFICANCE: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Quinases Relacionadas a NIMA/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Paclitaxel/farmacologia , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular Tumoral , Senescência Celular , Centrossomo/enzimologia , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Xenoenxertos , Humanos , Mitose/genética , Quinases Relacionadas a NIMA/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Taxoides/administração & dosagem , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Ensaio Tumoral de Célula-Tronco , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
PURPOSE: To (i) create a survival risk score using radiomic features from the tumor habitat on routine MRI to predict progression-free survival (PFS) in glioblastoma and (ii) obtain a biological basis for these prognostic radiomic features, by studying their radiogenomic associations with molecular signaling pathways. EXPERIMENTAL DESIGN: Two hundred three patients with pretreatment Gd-T1w, T2w, T2w-FLAIR MRI were obtained from 3 cohorts: The Cancer Imaging Archive (TCIA; n = 130), Ivy GAP (n = 32), and Cleveland Clinic (n = 41). Gene-expression profiles of corresponding patients were obtained for TCIA cohort. For every study, following expert segmentation of tumor subcompartments (necrotic core, enhancing tumor, peritumoral edema), 936 3D radiomic features were extracted from each subcompartment across all MRI protocols. Using Cox regression model, radiomic risk score (RRS) was developed for every protocol to predict PFS on the training cohort (n = 130) and evaluated on the holdout cohort (n = 73). Further, Gene Ontology and single-sample gene set enrichment analysis were used to identify specific molecular signaling pathway networks associated with RRS features. RESULTS: Twenty-five radiomic features from the tumor habitat yielded the RRS. A combination of RRS with clinical (age and gender) and molecular features (MGMT and IDH status) resulted in a concordance index of 0.81 (P < 0.0001) on training and 0.84 (P = 0.03) on the test set. Radiogenomic analysis revealed associations of RRS features with signaling pathways for cell differentiation, cell adhesion, and angiogenesis, which contribute to chemoresistance in GBM. CONCLUSIONS: Our findings suggest that prognostic radiomic features from routine Gd-T1w MRI may also be significantly associated with key biological processes that affect response to chemotherapy in GBM.
Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/mortalidade , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Mutação , Medição de Risco/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais , Taxa de Sobrevida , Adulto JovemRESUMO
Genome-scale studies focusing on molecular profiling of cancers across tissue types have revealed a plethora of aberrations across the genomic, transcriptomic, and epigenomic scales. The significant molecular heterogeneity across individual tumors even within the same tissue context complicates decoding the key etiologic mechanisms of this disease. Furthermore, it is increasingly likely that biologic mechanisms underlying the pathobiology of cancer involve multiple molecular entities interacting across functional scales. This has motivated the development of computational approaches that integrate molecular measurements with prior biological knowledge in increasingly intricate ways to enable the discovery of driver genomic aberrations across cancers. Here, we review diverse methodological approaches that have powered significant advances in our understanding of the genomic underpinnings of cancer at the cohort and at the individual tumor scales. We outline the key advances and challenges in the computational discovery of cancer mechanisms while motivating the development of systems biology approaches to comprehensively decode the biologic drivers of this complex disease.
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Carcinogênese/genética , Biologia Computacional , Neoplasias/genética , Transcriptoma/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Genômica , Humanos , Neoplasias/patologiaRESUMO
Monoclonal antibodies (mAbs) targeting the oncogenic receptor tyrosine kinase ERBB2/HER2, such as Trastuzumab, are the standard of care therapy for breast cancers driven by ERBB2 overexpression and activation. However, a substantial proportion of patients exhibit de novo resistance. Here, by comparing matched Trastuzumab-naive and post-treatment patient samples from a neoadjuvant trial, we link resistance with elevation of H3K27me3, a repressive histone modification catalyzed by polycomb repressor complex 2 (PRC2). In ErbB2+ breast cancer models, PRC2 silences endogenous retroviruses (ERVs) to suppress anti-tumor type-I interferon (IFN) responses. In patients, elevated H3K27me3 in tumor cells following Trastuzumab treatment correlates with suppression of interferon-driven viral defense gene expression signatures and poor response. Using an immunocompetent model, we provide evidence that EZH2 inhibitors promote interferon-driven immune responses that enhance the efficacy of anti-ErbB2 mAbs, suggesting the potential clinical benefit of epigenomic reprogramming by H3K27me3 depletion in Trastuzumab-resistant disease.
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Histonas/metabolismo , Lisina/metabolismo , Terapia de Alvo Molecular , Receptor ErbB-2/metabolismo , Adulto , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Interferon Tipo I/metabolismo , Metilação , Camundongos , Modelos Biológicos , Complexo Repressor Polycomb 2/metabolismo , Retroelementos/genética , Trastuzumab/uso terapêutico , Regulação para CimaRESUMO
Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Epigênese Genética , Complexo Repressor Polycomb 2/genética , Receptor ErbB-2/metabolismo , Quinases da Família src/metabolismo , Trifosfato de Adenosina/metabolismo , Adulto , Animais , Neoplasias da Mama/patologia , Proteína Tirosina Quinase CSK , Carcinogênese , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Biossíntese de Proteínas , Receptor ErbB-2/genética , Quinases da Família src/genéticaRESUMO
Importance: There has been significant recent interest in understanding the utility of quantitative imaging to delineate breast cancer intrinsic biological factors and therapeutic response. No clinically accepted biomarkers are as yet available for estimation of response to human epidermal growth factor receptor 2 (currently known as ERBB2, but referred to as HER2 in this study)-targeted therapy in breast cancer. Objective: To determine whether imaging signatures on clinical breast magnetic resonance imaging (MRI) could noninvasively characterize HER2-positive tumor biological factors and estimate response to HER2-targeted neoadjuvant therapy. Design, Setting, and Participants: In a retrospective diagnostic study encompassing 209 patients with breast cancer, textural imaging features extracted within the tumor and annular peritumoral tissue regions on MRI were examined as a means to identify increasingly granular breast cancer subgroups relevant to therapeutic approach and response. First, among a cohort of 117 patients who received an MRI prior to neoadjuvant chemotherapy (NAC) at a single institution from April 27, 2012, through September 4, 2015, imaging features that distinguished HER2+ tumors from other receptor subtypes were identified. Next, among a cohort of 42 patients with HER2+ breast cancers with available MRI and RNaseq data accumulated from a multicenter, preoperative clinical trial (BrUOG 211B), a signature of the response-associated HER2-enriched (HER2-E) molecular subtype within HER2+ tumors (n = 42) was identified. The association of this signature with pathologic complete response was explored in 2 patient cohorts from different institutions, where all patients received HER2-targeted NAC (n = 28, n = 50). Finally, the association between significant peritumoral features and lymphocyte distribution was explored in patients within the BrUOG 211B trial who had corresponding biopsy hematoxylin-eosin-stained slide images. Data analysis was conducted from January 15, 2017, to February 14, 2019. Main Outcomes and Measures: Evaluation of imaging signatures by the area under the receiver operating characteristic curve (AUC) in identifying HER2+ molecular subtypes and distinguishing pathologic complete response (ypT0/is) to NAC with HER2-targeting. Results: In the 209 patients included (mean [SD] age, 51.1 [11.7] years), features from the peritumoral regions better discriminated HER2-E tumors (maximum AUC, 0.85; 95% CI, 0.79-0.90; 9-12 mm from the tumor) compared with intratumoral features (AUC, 0.76; 95% CI, 0.69-0.84). A classifier combining peritumoral and intratumoral features identified the HER2-E subtype (AUC, 0.89; 95% CI, 0.84-0.93) and was significantly associated with response to HER2-targeted therapy in both validation cohorts (AUC, 0.80; 95% CI, 0.61-0.98 and AUC, 0.69; 95% CI, 0.53-0.84). Features from the 0- to 3-mm peritumoral region were significantly associated with the density of tumor-infiltrating lymphocytes (R2 = 0.57; 95% CI, 0.39-0.75; P = .002). Conclusions and Relevance: A combination of peritumoral and intratumoral characteristics appears to identify intrinsic molecular subtypes of HER2+ breast cancers from imaging, offering insights into immune response within the peritumoral environment and suggesting potential benefit for treatment guidance.
Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Imageamento por Ressonância Magnética/estatística & dados numéricos , Radiometria/estatística & dados numéricos , Receptor ErbB-2/metabolismo , Adulto , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Feminino , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Período Pré-Operatório , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Tumor-initiating cells (TICs) contribute to drug resistance and tumor recurrence in cancers, thus experimental approaches to dissect the complexity of TICs are required to design successful TIC therapeutic strategies. Here, we show that miRNA-3' UTR sensor vectors can be used as a pathway-based method to identify, enrich, and analyze TICs from primary solid tumor patient samples. We have found that an miR-181ahigh subpopulation of cells sorted from primary ovarian tumor cells exhibited TIC properties in vivo, were enriched in response to continuous cisplatin treatment, and showed activation of numerous major stem cell regulatory pathways. This miRNA-sensor-based platform enabled high-throughput drug screening leading to identification of BET inhibitors as transcriptional inhibitors of miR-181a. Taken together, we provide a valuable miRNA-sensor-based approach to broaden the understanding of complex TIC regulatory mechanisms in cancers and to identify miRNA-targeting drugs.
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Antineoplásicos/farmacologia , Técnicas Biossensoriais/métodos , Descoberta de Drogas/métodos , MicroRNAs/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Feminino , Humanos , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologiaRESUMO
Hypoxia, a characteristic trait of Glioblastoma (GBM), is known to cause resistance to chemo-radiation treatment and is linked with poor survival. There is hence an urgent need to non-invasively characterize tumor hypoxia to improve GBM management. We hypothesized that (a) radiomic texture descriptors can capture tumor heterogeneity manifested as a result of molecular variations in tumor hypoxia, on routine treatment naïve MRI, and (b) these imaging based texture surrogate markers of hypoxia can discriminate GBM patients as short-term (STS), mid-term (MTS), and long-term survivors (LTS). 115 studies (33 STS, 41 MTS, 41 LTS) with gadolinium-enhanced T1-weighted MRI (Gd-T1w) and T2-weighted (T2w) and FLAIR MRI protocols and the corresponding RNA sequences were obtained. After expert segmentation of necrotic, enhancing, and edematous/nonenhancing tumor regions for every study, 30 radiomic texture descriptors were extracted from every region across every MRI protocol. Using the expression profile of 21 hypoxia-associated genes, a hypoxia enrichment score (HES) was obtained for the training cohort of 85 cases. Mutual information score was used to identify a subset of radiomic features that were most informative of HES within 3-fold cross-validation to categorize studies as STS, MTS, and LTS. When validated on an additional cohort of 30 studies (11 STS, 9 MTS, 10 LTS), our results revealed that the most discriminative features of HES were also able to distinguish STS from LTS (p = 0.003).
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Adulto , Idoso , Biomarcadores , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/mortalidade , Feminino , Perfilação da Expressão Gênica , Genômica/métodos , Glioblastoma/diagnóstico por imagem , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Transdução de SinaisRESUMO
Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. Although BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks an SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi. Cancer Res; 77(19); 5395-408. ©2017 AACR.
Assuntos
Mitose/efeitos dos fármacos , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas Supressoras de Tumor/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Identifying subsets of genes that jointly mediate cancer etiology, progression, or therapy response remains a challenging problem due to the complexity and heterogeneity in cancer biology, a problem further exacerbated by the relatively small number of cancer samples profiled as compared with the sheer number of potential molecular factors involved. Pure data-driven methods that merely rely on multiomics data have been successful in discovering potentially functional genes but suffer from high false-positive rates and tend to report subsets of genes whose biological interrelationships are unclear. Recently, integrative data-driven models have been developed to integrate multiomics data with signaling pathway networks in order to identify pathways associated with clinical or biological phenotypes. However, these approaches suffer from an important drawback of being restricted to previously discovered pathway structures and miss novel genomic interactions as well as potential crosstalk among the pathways. In this article, we propose a novel coalition-based game-theoretic approach to overcome the challenge of identifying biologically relevant gene subnetworks associated with disease phenotypes. The algorithm starts from a set of seed genes and traverses a protein-protein interaction network to identify modulated subnetworks. The optimal set of modulated subnetworks is identified using Shapley value that accounts for both individual and collective utility of the subnetwork of genes. The algorithm is applied to two illustrative applications, including the identification of subnetworks associated with (i) disease progression risk in response to platinum-based therapy in ovarian cancer and (ii) immune infiltration in triple-negative breast cancer. The results demonstrate an improved predictive power of the proposed method when compared with state-of-the-art feature selection methods, with the added advantage of identifying novel potentially functional gene subnetworks that may provide insights into the mechanisms underlying cancer progression.