New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer

Nature Reviews Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 20(2), P. 69 - 84

Published: Nov. 20, 2018

Language: Английский

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The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers

Nature reviews. Cancer, Journal Year: 2018, Volume and Issue: 18(11), P. 696 - 705

Published: Oct. 6, 2018

Language: Английский

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Tumour-intrinsic resistance to immune checkpoint blockade

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 20(1), P. 25 - 39

Published: Sept. 30, 2019

Language: Английский

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Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update

Nature Reviews Clinical Oncology, Journal Year: 2019, Volume and Issue: 17(4), P. 204 - 232

Published: Dec. 2, 2019

Language: Английский

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Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?

American Society of Clinical Oncology Educational Book, Journal Year: 2019, Volume and Issue: 39, P. 147 - 164

Published: May 1, 2019

The emergence of immune checkpoint blockade therapies over the last decade has transformed cancer treatment in a wide range tumor types. Unprecedented and durable clinical responses difficult-to-treat histologies have been observed. However, despite these promising long-term responses, majority patients fail to respond blockade, demonstrating primary resistance. Additionally, many those who initially eventually experience relapse secondary acquired Both resistance are result complex constantly evolving interactions between cells system. Many mechanisms characterized date, more continue be uncovered. By elucidating targeting resistance, treatments can tailored improve outcomes. This review will discuss landscape response data, different mechanisms, potential therapeutic strategies overcome

Language: Английский

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The impact of sex on gene expression across human tissues

Science, Journal Year: 2020, Volume and Issue: 369(6509)

Published: Sept. 10, 2020

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex in gene expression and genetic regulation across 44 tissue sources surveyed by Genotype-Tissue Expression project (GTEx, v8 release). demonstrate that influences levels cellular composition samples body. A total 37% all genes sex-biased at least one tissue. identify cis quantitative trait loci (eQTLs) with effects characterize their origin. By integrating eQTLs genome-wide association study data, we 58 gene-trait associations are driven single sex. These findings provide an extensive characterization transcriptome its regulation.

Language: Английский

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Acquisition of a hybrid E/M state is essential for tumorigenicity of basal breast cancer cells

Proceedings of the National Academy of Sciences, Journal Year: 2019, Volume and Issue: 116(15), P. 7353 - 7362

Published: March 25, 2019

Carcinoma cells residing in an intermediate phenotypic state along the epithelial–mesenchymal (E–M) spectrum are associated with malignant phenotypes, such as invasiveness, tumor-initiating ability, and metastatic dissemination. Using recently described CD104 + /CD44 hi antigen marker combination, we isolated highly tumorigenic breast cancer stably—both vitro vivo—in coexpressing both epithelial (E) mesenchymal (M) markers. We demonstrate that tumorigenicity depends on individual this E/M hybrid cannot be phenocopied by mixing two cell populations reside stably at ends of spectrum, i.e., E M state. Hence, residence a specific E–M rather than plasticity appears critical to expression capacity. Acquisition is facilitated differential EMT-inducing transcription factors (EMT-TFs) accompanied adult stem programs, notably, active canonical Wnt signaling. Furthermore, transition from fully phenotype, achieved constitutive ectopic Zeb1, sufficient drive out into state, which substantial loss switch noncanonical Identifying gatekeepers various states arrayed likely prove useful developing therapeutic approaches operate shifting between distinct spectrum.

Language: Английский

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Developmental pathways in the pathogenesis of lung fibrosis

Molecular Aspects of Medicine, Journal Year: 2018, Volume and Issue: 65, P. 56 - 69

Published: Aug. 23, 2018

Language: Английский

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Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (Review)

International Journal of Oncology, Journal Year: 2017, Volume and Issue: 51(5), P. 1357 - 1369

Published: Sept. 19, 2017

Cancer stem cells (CSCs), which have the potential for self-renewal, differentiation and de-differentiation, undergo epigenetic, epithelial-mesenchymal, immunological metabolic reprogramming to adapt tumor microenvironment survive host defense or therapeutic insults. Intra-tumor heterogeneity cancer-cell plasticity give rise resistance recurrence through clonal replacement reactivation of dormant CSCs, respectively. WNT signaling cascades cross-talk with FGF, Notch, Hedgehog TGFβ/BMP regulate expression functional CSC markers, such as CD44, CD133 (PROM1), EPCAM LGR5 (GPR49). Aberrant canonical non-canonical in human malignancies, including breast, colorectal, gastric, lung, ovary, pancreatic, prostate uterine cancers, leukemia melanoma, are involved survival, bulk-tumor expansion invasion/metastasis. signaling-targeted therapeutics, anti-FZD1/2/5/7/8 monoclonal antibody (mAb) (vantictumab), anti-LGR5 antibody-drug conjugate (ADC) (mAb-mc-vc-PAB-MMAE), anti-PTK7 ADC (PF-06647020), anti-ROR1 mAb (cirmtuzumab), anti-RSPO3 (rosmantuzumab), small-molecule porcupine inhibitors (ETC-159, WNT-C59 WNT974), tankyrase (AZ1366, G007-LK, NVP-TNKS656 XAV939) β-catenin (BC2059, CWP232228, ICG-001 PRI-724), clinical trials preclinical studies treatment patients WNT-driven cancers. therapeutics applicable combination therapy BCR-ABL, EGFR, FLT3, KIT RET treat a subset tyrosine kinase-driven cancers because kinase converge maintenance CSCs. might also be immune checkpoint blockers, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab pembrolizumab, evasion, although context-dependent effects on immunity should carefully assessed. Omics monitoring, genome sequencing transcriptome tests, immunohistochemical analyses PD-L1 (CD274), PD-1 (PDCD1), ROR1 nuclear organoid-based drug screening, is necessary determine appropriate cancer patients.

Language: Английский

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MYC Deregulation in Primary Human Cancers

Genes, Journal Year: 2017, Volume and Issue: 8(6), P. 151 - 151

Published: May 25, 2017

MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, is master regulator of many processes, including cell cycle entry, ribosome biogenesis, metabolism. In cancer, the activity transcriptional network frequently deregulated, contributing to initiation maintenance disease. Deregulation often leads constitutive overexpression MYC, which can be achieved through gross genetic abnormalities, copy number alterations, chromosomal translocations, increased enhancer activity, or aberrant signal transduction leading transcription mRNA protein stability. Herein, we summarize frequency modes deregulation describe both well-established more recent findings in variety cancer types. Notably, these studies have highlighted that with an appreciation for basic mechanisms deregulating new therapeutic vulnerabilities discovered potentially exploited inhibition this potent oncogene cancer.

Language: Английский

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