The Immune Landscape of Cancer

Immunity, Год журнала: 2018, Номер 48(4), С. 812 - 830.e14

Опубликована: Апрель 1, 2018

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled TCGA. Across types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized differences in macrophage or signatures, Th1:Th2 cell ratio, extent intratumoral heterogeneity, aneuploidy, neoantigen load, overall proliferation, expression immunomodulatory genes, prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, IDH1) higher (BRAF, TP53, CASP8) leukocyte levels across all cancers. Multiple control modalities the intracellular extracellular networks (transcription, microRNAs, copy number, epigenetic processes) were involved tumor-immune interactions, both within subtypes. Our immunogenomics pipeline to characterize these heterogeneous resulting are intended serve as a resource for future targeted studies further advance field.

Язык: Английский

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Pan-cancer analysis of whole genomes

Nature, Год журнала: 2020, Номер 578(7793), С. 82 - 93

Опубликована: Фев. 5, 2020

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation this variation at whole-genome scale 1–3 . Here we report integrative analysis 2,658 whole-cancer genomes their matching normal tissues across 38 tumour types from Pan-Cancer Analysis Whole Genomes (PCAWG) Consortium International Genome (ICGC) The Atlas (TCGA). We describe generation PCAWG resource, facilitated international data sharing using compute clouds. On average, cancer contained 4–5 driver mutations when combining coding non-coding genomic elements; however, in around 5% cases no drivers were identified, suggesting that discovery not yet complete. Chromothripsis, which many clustered structural variants arise a single catastrophic event, frequently an early event evolution; acral melanoma, for example, these events precede most somatic point affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate low replicative activity show mechanisms preventing attrition to critical levels. Common rare germline patterns mutation, including mutations, retrotransposition. A collection papers describes drive beyond those TERT promoter 4 ; identifies new signatures mutational processes cause base substitutions, small insertions deletions 5,6 analyses timings evolution 7 diverse transcriptional consequences mutation on splicing, expression levels, fusion 8,9 evaluates range more-specialized features 8,10–18

Язык: Английский

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Hepatocellular carcinoma

The Lancet, Год журнала: 2022, Номер 400(10360), С. 1345 - 1362

Опубликована: Сен. 6, 2022

Язык: Английский

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ERK/MAPK signalling pathway and tumorigenesis (Review)

Experimental and Therapeutic Medicine, Год журнала: 2020, Номер unknown

Опубликована: Янв. 15, 2020

Mitogen‑activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, kinase, MAPK, which activate phosphorylate downstream proteins. extracellular signal‑regulated kinases ERK1 ERK2 evolutionarily conserved, ubiquitous serine‑threonine under both normal pathological conditions. ERK expression is critical for development their hyperactivation plays major role in cancer progression. Ras/Raf/MAPK (MEK)/ERK the most important cascade among all signal transduction pathways, crucial survival tumour cells. present review discusses recent studies on Ras members. With respect to processes activation, invasion metastasis highlighted, ERK/MAPK matrix degradation angiogenesis emphasised.

Язык: Английский

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Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases

Nature Reviews Drug Discovery, Год журнала: 2019, Номер 18(4), С. 295 - 317

Опубликована: Янв. 4, 2019

Язык: Английский

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The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients

Cancer Discovery, Год журнала: 2019, Номер 10(1), С. 54 - 71

Опубликована: Окт. 29, 2019

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, inhibits KRAS-dependent signaling. demonstrated pronounced tumor regression 17 26 (65%) KRASG12C-positive cell line- patient-derived xenograft models from multiple types, objective responses observed patients with lung colon adenocarcinomas. Comprehensive pharmacodynamic pharmacogenomic profiling sensitive partially resistant nonclinical mechanisms implicated limiting antitumor activity including nucleotide cycling pathways induce feedback reactivation and/or bypass dependence. These factors included activation receptor tyrosine kinases (RTK), dependence, genetic dysregulation cycle. Combinations agents RTKs, mTOR, or cycle enhanced response marked several models, MRTX849-refractory models. SIGNIFICANCE: The discovery provides long-awaited opportunity patients. in-depth characterization activity, elucidation resistance mechanisms, identification effective combinations provide new insight toward dependence the rational development this class agents.See related commentary by Klempner Hata, p. 20.This article is highlighted In This Issue feature, 1.

Язык: Английский

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The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway

Molecular and Cellular Biology, Год журнала: 2020, Номер 40(13)

Опубликована: Апрель 14, 2020

The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates activity transcription factor NRF2 by targeting it for ubiquitination proteasome-dependent degradation. In stress, intricate molecular mechanism facilitated sensor cysteines within allows escape ubiquitination, accumulate cell, translocate nucleus, where can promote its antioxidant program. Recent advances have revealed that contains multiple stress sensors inactivation modalities, together allow diverse cellular inputs, from metabolites dysregulated autophagy, regulate activity. This integration system into signaling metabolic pathways places activation as a critical regulatory node in many disease phenotypes suggests pharmaceutical modulation NRF2's cytoprotective will be beneficial human health broad range noncommunicable diseases.

Язык: Английский

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The Hippo Pathway: Biology and Pathophysiology

Annual Review of Biochemistry, Год журнала: 2018, Номер 88(1), С. 577 - 604

Опубликована: Дек. 19, 2018

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size control, regeneration. core the mammals consists kinase cascade, MST1/2 LATS1/2, well downstream effectors, transcriptional coactivators YAP TAZ. These components control programs involved proliferation, survival, mobility, stemness, differentiation. tightly regulated by both intrinsic extrinsic signals, such mechanical force, cell-cell contact, polarity, energy status, stress, many diffusible hormonal factors, majority which act through G protein-coupled receptors. Here, we review current understanding molecular mechanisms signals regulate with emphasis on mechanotransduction effects this basic biology human diseases.

Язык: Английский

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A compendium of mutational cancer driver genes

Nature reviews. Cancer, Год журнала: 2020, Номер 20(10), С. 555 - 572

Опубликована: Авг. 10, 2020

Язык: Английский

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Cell cycle control in cancer

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 23(1), С. 74 - 88

Опубликована: Сен. 10, 2021

Язык: Английский

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