PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Янв. 10, 2020

Abstract mTORC1 is an important regulator of muscle mass but how it modulated by oxygen and nutrients not completely understood. We show that loss the prolyl hydroxylase domain isoform 1 sensor in mice (PHD1 KO ) reduces mass. PHD1 muscles impaired activation response to leucine whereas growth factors or eccentric contractions was preserved. The ability promote activity independent its hydroxylation caused decreased protein content leucyl tRNA synthetase (LRS) sensor. Mechanistically, interacts with stabilizes LRS. This interaction promoted during amino acid depletion protects LRS from degradation. Finally, elderly subjects have lower levels aged versus young human subjects. In conclusion, ensures optimal after episodes metabolic scarcity.

Язык: Английский

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Molecular principles of metastasis: a hallmark of cancer revisited

Signal Transduction and Targeted Therapy, Год журнала: 2020, Номер 5(1)

Опубликована: Март 12, 2020

Abstract Metastasis is the hallmark of cancer that responsible for greatest number cancer-related deaths. Yet, it remains poorly understood. The continuous evolution biology research and emergence new paradigms in study metastasis have revealed some molecular underpinnings this dissemination process. invading tumor cell, on its way to target site, interacts with other proteins cells. Recognition these interactions improved understanding biological principles metastatic cell govern mobility plasticity. Communication microenvironment allows cells overcome stromal challenges, settle, colonize. These characteristics are driven by genetic epigenetic modifications within itself microenvironment. Establishing mechanisms process crucial finding open therapeutic windows successful interventions. In review, authors explore recent advancements field highlight latest insights contribute shaping cancer.

Язык: Английский

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Cancer stem cells as key drivers of tumour progression

Journal of Biomedical Science, Год журнала: 2018, Номер 25(1)

Опубликована: Март 6, 2018

Cancer stem cells (CSCs) are subpopulations of cancer sharing similar characteristics as normal or progenitor such self-renewal ability and multi-lineage differentiation to drive tumour growth heterogeneity. Throughout the progression, CSC can further be induced from differentiated via adaptation cross-talks with microenvironment well a response therapeutic pressures, therefore contributes their heterogeneous phenotypes. Challengingly, conventional treatments target bulk unable CSCs due highly resistance nature, leading metastasis recurrence.

Язык: Английский

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Cancer Stem Cells: Basic Concepts and Therapeutic Implications

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2016, Номер 11(1), С. 47 - 76

Опубликована: Май 19, 2016

Different mechanisms contribute to intratumor heterogeneity, including genetic mutations, the microenvironment, and existence of subpopulations cancer cells with increased renewal capacity ability recapitulate heterogeneity found in primary tumors, which are referred as stem (CSCs). In this review, we discuss how concept CSCs has been defined, what assays currently used define functional properties CSCs, intrinsic extrinsic regulate CSC functions, plastic are, importance epithelial-to-mesenchymal transition conferring properties. Finally, by may resist medical therapy tumor relapse.

Язык: Английский

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Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

Frontiers in Oncology, Год журнала: 2015, Номер 5

Опубликована: Янв. 1, 2015

Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical decision that cells undergo Epithelial-to-Mesenchymal Transition (EMT) its reverse Mesenchymal-to-Epithelial (MET). While transitioning between these two phenotypes – epithelial mesenchymal, can also attain hybrid epithelial/ mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells this phenotype have mixed (eg. adhesion) migration) properties, thereby allowing them to move collectively as clusters of Circulating Tumor (CTCs). If enter the circulation, they be more apoptosis-resistant capable initiating metastatic lesions than moving individually with wholly phenotypes, having undergone complete EMT. Here, we review operating principles core regulatory network for EMT/MET acts ‘three-way’ switch giving rise three distinct epithelial, epithelial/mesenchymal. We further characterize E/M terms capabilities collective cell migration, tumor-initiation, cell-cell communication, drug resistance. elucidate how highly interconnected coupling modules coordinates among population dynamic tumor, hence facilitating tumor-stroma interactions, formation CTC clusters, consequently metastasis. Finally, discuss multiple advantages epithelial/mesenchymal compared EMT argue migrating are primary ‘bad actors’

Язык: Английский

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Interrogating open issues in cancer precision medicine with patient-derived xenografts

Nature reviews. Cancer, Год журнала: 2017, Номер 17(4), С. 254 - 268

Опубликована: Янв. 20, 2017

Язык: Английский

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Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer

JAMA Oncology, Год журнала: 2016, Номер 2(11), С. 1441 - 1441

Опубликована: Июнь 4, 2016

A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane.To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) treatment-specific marker for response outcomes between ARS inhibitors taxanes.For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing change treatment were considered; 86 excluded because they not initiating taxane therapy; 18 processing time constraints, leaving 161 patients analysis. Between December 2012 March 2015, blood was collected processed from immediately prior new line systemic therapy. Patients followed up 3 years.Prostate-specific antigen (PSA) response, receiving therapy, radiographic progression-free survival (rPFS), overall (OS).Overall, 193 prospectively samples mCRPC, 191 evaluable (128 pre-ARS 63 pretaxane). AR-V7-positive CTCs found 34 (18%), including 3% first-line, 18% second-line, 31% third- greater samples. whose had before inhibition resistant posttherapy PSA changes (PTPC), shorter rPFS, OS than those without CTCs. Overall, PTPC seen 65 112 (58%) detectable inhibition. There statistically significant differences but PTPC, rPFS treated taxane. multivariable model adjusting baseline factors associated showed superior taxanes relative detected (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035).The results validate CTC AR-V7 as biomarker that therapy over ARS-directed clinical practice setting. Continued examination prospective studies will further aid utility.

Язык: Английский

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Circulating and disseminated tumour cells — mechanisms of immune surveillance and escape

Nature Reviews Clinical Oncology, Год журнала: 2016, Номер 14(3), С. 155 - 167

Опубликована: Сен. 20, 2016

Язык: Английский

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Stability of the hybrid epithelial/mesenchymal phenotype

Oncotarget, Год журнала: 2016, Номер 7(19), С. 27067 - 27084

Опубликована: Март 17, 2016

Epithelial-to-Mesenchymal Transition (EMT) and its reverse - Mesenchymal to Epithelial (MET) are hallmarks of cellular plasticity during embryonic development cancer metastasis. During EMT, epithelial cells lose cell-cell adhesion gain migratory invasive traits either partially or completely, leading a hybrid epithelial/mesenchymal (hybrid E/M) mesenchymal phenotype respectively. move individually, but E/M migrate collectively as observed gastrulation, wound healing, the formation tumor clusters detected Circulating Tumor Cells (CTCs). Typically, has largely been tacitly assumed be transient 'metastable'. Here, we identify certain 'phenotypic stability factors' (PSFs) such GRHL2 that couple core EMT decision-making circuit (miR-200/ZEB) stabilize phenotype. Further, show H1975 lung can display stable collectively, behavior is impaired by knockdown another previously identified PSF OVOL. In addition, our computational model predicts also associate with high tumor-initiating potential, prediction strengthened observation higher levels these PSFs may predictive poor patient outcome. Finally, based on specific examples, deduce network motifs Our results suggest partial i.e. phenotype, need not 'metastable', strengthen emerging notion necessarily complete associated aggressive progression.

Язык: Английский

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Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management

Computational and Structural Biotechnology Journal, Год журнала: 2018, Номер 16, С. 370 - 378

Опубликована: Янв. 1, 2018

Precision medicine in the clinical management of cancer may be achieved through diagnostic platform called "liquid biopsy". This method utilizes detection biomarkers blood for prognostic and predictive purposes. One latest born markers under investigation field liquid biopsy patients is circulating tumor DNA (ctDNA). ctDNA released by cells different mechanisms can therefore provide information about genomic make-up currently present patient. Through longitudinal ctDNA-based biopsies, dynamics monitored to predict assess drug response and/or resistance. However, because highly fragmented its concentration extremely low a high background normal DNA, screening relevant mutations challenging. Although significant progress has been made advancing analysis last few years, current challenges include standardization increasing techniques single molecule sensitivity combination with perfect specificity. review focuses on potential role patients, technologies that are being employed, hurdles still need taken achieve towards precision medicine.

Язык: Английский

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