Translational Control in Tumour Progression and Drug Resistance

Reprogramming of energetic metabolism is a phenotypic trait of cancer in which mitochondrial dysfunction represents a key event in tumour progression. In the present study, we show that the acquisition of the tumour-promoting phenotype in colon cancer HCT116 cells treated with oligomycin to inhibit ATP synthase is exerted by repression of the synthesis of nuclear-encoded mitochondrial proteins in a process that is regulated at the level of translation. Remarkably, the synthesis of glycolytic proteins is not affected in this situation. Changes in translational control of mitochondrial proteins are signalled by the activation of AMPK (AMP-activated protein kinase) and the GCN2 (general control non-derepressible 2) kinase, leading also to the activation of autophagy. Changes in the bioenergetic function of mitochondria are mimicked by the activation of AMPK and the silencing of ATF4 (activating transcription factor 4). These findings emphasize the relevance of translational control for normal mitochondrial function and for the progression of cancer. Moreover, they demonstrate that glycolysis and oxidative phosphorylation are controlled at different levels of gene expression, offering the cell a mechanistic safeguard strategy for metabolic adaptation under stressful conditions.

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SmartCodes: functionalized barcodes that enable targeted retrieval of clonal lineages from a heterogeneous population

10.1101/352617 ◽

2018 ◽

Cited By ~ 5

Author(s):

Clare Rebbeck ◽

Florian Raths ◽

Bassem Ben Cheik ◽

Kenneth Gouin ◽

Gregory J. Hannon ◽

...

Keyword(s):

Drug Resistance ◽

Single Cell ◽

Tumour Progression ◽

Complex Mixture ◽

Heterogeneous Population ◽

Complex Mixtures ◽

Tumour Heterogeneity ◽

Selectable Markers ◽

Molecular Barcoding ◽

Molecular Barcode

AbstractMolecular barcoding has provided means to link genotype to phenotype, to individuate cells in single-cell analyses, to enable the tracking of evolving lineages, and to facilitate the analysis of complex mixtures containing phenotypically distinct lineages. To date, all existing approaches enable retrospective associations to be made between characteristics and the lineage harbouring them, but provide no path toward isolating or manipulating those lineages within the complex mixture. Here, we describe a strategy for creating functionalized barcodes that enable straightforward manipulation of lineages within complex populations of cells, either marking and retrieval of selected lineages, or modification of their phenotype within the population, including their elimination. These “SmartCodes” rely on a simple CRISPR-based, molecular barcode reader that can switch measurable, or selectable markers, on or off in a binary fashion. While this approach could have broad impact, we envision initial approaches to the study of tumour heterogeneity, focused on issues of tumour progression, metastasis, and drug resistance.

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Regulation of Translation in the Protozoan Parasite Leishmania

International Journal of Molecular Sciences ◽

10.3390/ijms21082981 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2981

Author(s):

Zemfira N. Karamysheva ◽

Sneider Alexander Gutierrez Guarnizo ◽

Andrey L. Karamyshev

Keyword(s):

Drug Resistance ◽

Translational Control ◽

Transcriptional Control ◽

Molecular Mechanisms ◽

Rna Binding ◽

Rna Binding Proteins ◽

Protozoan Parasite ◽

Sand Fly ◽

Mammalian Host ◽

Translational Machinery

Leishmaniasis represents a serious health problem worldwide and drug resistance is a growing concern. Leishmania parasites use unusual mechanisms to control their gene expression. In contrast to many other species, they do not have transcriptional regulation. The lack of transcriptional control is mainly compensated by post-transcriptional mechanisms, including tight translational control and regulation of mRNA stability/translatability by RNA-binding proteins. Modulation of translation plays a major role in parasite survival and adaptation to dramatically different environments during change of host; however, our knowledge of fine molecular mechanisms of translation in Leishmania remains limited. Here, we review the current progress in our understanding of how changes in the translational machinery promote parasite differentiation during transmission from a sand fly to a mammalian host, and discuss how translational reprogramming can contribute to the development of drug resistance.

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Stem Cells in Tumour Microenvironment Aid in Prolonged Survival Rate of Cancer Cells and Developed Drug Resistance: Major Challenge in Osteosarcoma Treatment

Current Drug Metabolism ◽

10.2174/1389200221666200214120226 ◽

2020 ◽

Vol 21 (1) ◽

pp. 44-52

Author(s):

Bhaskar Birru ◽

ChandraSai Potla Durthi ◽

Santhosh Kacham ◽

Madhuri Pola ◽

Satish Babu Rajulapati ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Tumour Progression ◽

Combined Treatment ◽

Bone Cancer ◽

Tumour Microenvironment ◽

Surgical Removal ◽

Therapeutic Approaches ◽

Hypoxic Environment

Osteosarcoma is an aggressive bone cancer found in children and adolescents. The combined treatment strategy includes the surgical removal of tumour and subsequent chemotherapy to prevent the reoccurrence has been a widely accepted approach. However, the drug resistance developed by tumour cells causes recurrence of cancer. It is imperative to understand the molecular mechanism involved in the development of drug resistance and tumour progression for developing potential therapy. Tumour microenvironment and cellular cross-talk via activation of various signalling pathways are responsible for tumour progression and metastasis. The comprehensive reviews are already available on the tumour microenvironment, signalling cascades responsible for tumour progression, and cellular crosstalk between malignant cells and immune cells. Therefore, we intend to provide comprehend review postulating the importance of mesenchymal stem cells (MSCs) in osteosarcoma progression and metastasis. This paper is aimed to provide information sequentially includes: tumour microenvironment, MSCs role in osteosarcoma progression, the hypoxic environment in MSCs recruitment at the tumour site and the importance of exosomes in tumorigenesis, progression and metastasis. Overall, this review may enlighten the research on the role of MSCs and MSCs derived exosome in osteosarcoma progression and drug resistance. This possibly may result in developing novel therapeutic approaches to combat the osteosarcoma effectively and contributes for the development of prognosis tools for early diagnosis.

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Novel functions for Rab GTPases in multiple aspects of tumour progression

Biochemical Society Transactions ◽

10.1042/bst20120199 ◽

2012 ◽

Vol 40 (6) ◽

pp. 1398-1403 ◽

Cited By ~ 60

Author(s):

Chiara Recchi ◽

Miguel C. Seabra

Keyword(s):

Drug Resistance ◽

Cell Migration ◽

Anticancer Drugs ◽

Tumour Cell ◽

Stromal Cells ◽

Intracellular Trafficking ◽

Tumour Progression ◽

Rab Proteins ◽

Rab Gtpases ◽

Master Regulators

Rab GTPases are master regulators of intracellular trafficking and, in recent years, their role in the control of different aspects of tumour progression has emerged. In the present review, we show that Rab GTPases are disregulated in many cancers and have central roles in tumour cell migration, invasion, proliferation, communication with stromal cells and the development of drug resistance. As a consequence, Rab proteins may be novel potential candidates for the development of anticancer drugs and, in this context, the preliminary results obtained with an inhibitor of Rab function are also discussed.

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Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

10.1101/2020.12.18.423280 ◽

2020 ◽

Author(s):

Manasi K. Mayekar ◽

Deborah R. Caswell ◽

Natalie I. Vokes ◽

Emily K. Law ◽

Wei Wu ◽

...

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Targeted Therapy ◽

Cancer Therapy ◽

De Novo ◽

Tumour Progression ◽

Genetic Alterations ◽

Model Systems ◽

Clinical Samples ◽

Targeted Cancer Therapy

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-κB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

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MicroRNA-221-3p is related to survival and promotes tumour progression in pancreatic cancer: a comprehensive study on functions and clinicopathological value

Cancer Cell International ◽

10.1186/s12935-020-01529-9 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Xuejiao Wu ◽

Jia Huang ◽

Zilin Yang ◽

Ying Zhu ◽

Yongping Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Drug Resistance ◽

Tumour Progression ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Hub Genes ◽

Migration Ability ◽

Network Analyses ◽

Cancer Pathogenesis ◽

Genes Expression

Abstract Background The microRNA miR-221-3p has previously been found to be an underlying biomarker of pancreatic cancer. However, the mechanisms of miR-221-3p underlying its role in pancreatic cancer pathogenesis, proliferation capability, invasion ability, drug resistance and apoptosis and the clinicopathological value of miR-221-3p have not been thoroughly studied. Methods Based on microarray and miRNA-sequencing data extracted from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), relevant literature, and real-time quantitative PCR (RT-qPCR), we explored clinicopathological features and the expression of miR-221-3p to determine its clinical effect in pancreatic cancer. Proliferation, migration, invasion, apoptosis and in vitro cytotoxicity tests were selected to examine the roles of mir-221-3p. In addition, several miR-221-3p functional analyses were conducted, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein–protein interaction (PPI) network analyses, to examine gene interactions with miR-221-3p. Results The findings of integrated multi-analysis revealed higher miR-221-3p expression in pancreatic cancer tissues and blood than that in para-carcinoma samples (SMD of miR-221-3p: 1.52; 95% CI 0.96, 2.08). MiR-221-3p is related to survival both in pancreatic cancer and pancreatic ductal adenocarcinoma patients. Cell experiments demonstrated that miR-221-3p promotes pancreatic cancer cell proliferation capability, migration ability, invasion ability, and drug resistance but inhibits apoptosis. Further pancreatic cancer bioinformatics analyses projected 30 genes as the underlying targets of miR-221-3p. The genes were significantly distributed in diverse critical pathways, including microRNAs in cancer, viral carcinogenesis, and the PI3K-Akt signalling pathway. Additionally, PPI indicated four hub genes with threshold values of 5: KIT, CDKN1B, RUNX2, and BCL2L11. Moreover, cell studies showed that miR-221-3p can inhibit these four hub genes expression in pancreatic cancer. Conclusions Our research revealed that pancreatic cancer expresses a high-level of miR-221-3p, indicating a potential miR-221-3p role as a prognosis predictor in pancreatic cancer. Moreover, miR-221-3p promotes proliferation capacity, migration ability, invasion ability, and drug resistance but inhibits apoptosis in pancreatic cancer. The function of miR-221-3p in the development of pancreatic cancer may be mediated by the inhibition of hub genes expression. All these results might provide an opportunity to extend the understanding of pancreatic cancer pathogenesis.

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The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression

British Journal of Cancer ◽

10.1038/bjc.2012.201 ◽

2012 ◽

Vol 106 (12) ◽

pp. 1901-1906 ◽

Cited By ~ 83

Author(s):

J M Houthuijzen ◽

L G M Daenen ◽

J M L Roodhart ◽

E E Voest

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Mesenchymal Stem Cells ◽

Tumour Progression ◽

Cancer Drug ◽

Cancer Drug Resistance ◽

Anti Cancer

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DDRE-37. YB-1 AS A BIOMARKER FOR DRUG RESISTANCE AND TUMOUR PROGRESSION IN MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.321 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi82-vi82

Author(s):

Louisa Taylor ◽

Ian Kerr ◽

Beth Coyle

Keyword(s):

Drug Resistance ◽

Cell Lines ◽

Large Scale ◽

Tumour Progression ◽

Genomic Analysis ◽

Immunohistochemical Analysis ◽

Therapy Resistance ◽

Cellular Stress Response ◽

Nuclear Accumulation ◽

Poor Overall Survival

Abstract Medulloblastoma (MB) relapse is the most significant unmet clinical challenge in childhood cancer. Recently it has become evident that MBs display altered biology at relapse, indicative of the emergence and expansion of a minor, therapy resistant cancer cell population. Thus, the examination of mechanisms underlying therapy resistance is of critical importance. Y-box binding protein 1 (YB-1) is a multi-functional oncoprotein whose elevated expression and nuclear accumulation correlate with drug resistance, metastasis and disease progression in numerous cancers, although little is known about the functional role of YB-1 in MB. Genomic analysis of large-scale publicly available patient datasets revealed YB-1 expression is significantly elevated across MB molecular subgroups and high expression correlates with poor overall survival. Immunohistochemical analysis of YB-1 localisation in patient TMAs revealed significant YB-1 nuclear accumulation, suggestive of elevated YB-1 nuclear activity in these patients. Treatment of Group 3 MB cell lines (D283MED and HDMB-03) with cisplatin and subsequent analysis by nuclear/cytoplasmic fractionation and confocal microscopy revealed significantly increased nuclear and overall YB-1 expression, indicating a role for YB-1 in cellular stress response. In support of this, ChIP analysis in D283MED and HDMB-03 cell lines confirmed YB-1 interaction with multi-drug transporter gene ABCB1, while stable YB-1 knockdown resulted in significantly reduced ABCB1 expression. Likewise, knockdown of YB-1 expression in D283MED cells results in increased susceptibility of cells to vincristine, supporting a role for YB-1 in the acquisition of drug resistance in MB cell lines. Finally, whole transcriptome sequencing of YB-1-knockdown HDMB-03 and D283MED cell lines indicated YB-1 regulation of a variety of cell death, survival and metabolic pathways. We are currently using ChIP-Seq analysis to identify targetable YB-1 downstream “hits” which drive these processes. Ultimately, we aim to identify druggable targets of YB-1 allowing us to establish more effective therapeutic options for the treatment of high-risk MB.

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An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields

Cancers ◽

10.3390/cancers13194969 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4969

Author(s):

Sven Beyes ◽

Naiara Garcia Bediaga ◽

Alessio Zippo

Keyword(s):

Drug Resistance ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Tumour Progression ◽

Tumour Microenvironment ◽

Genetic Alterations ◽

Epigenetic Changes ◽

Multiple Cancer ◽

Tumour Heterogeneity

Cancer is a group of heterogeneous diseases that results from the occurrence of genetic alterations combined with epigenetic changes and environmental stimuli that increase cancer cell plasticity. Indeed, multiple cancer cell populations coexist within the same tumour, favouring cancer progression and metastatic dissemination as well as drug resistance, thereby representing a major obstacle for treatment. Epigenetic changes contribute to the onset of intra-tumour heterogeneity (ITH) as they facilitate cell adaptation to perturbation of the tumour microenvironment. Despite being its central role, the intrinsic multi-layered and reversible epigenetic pattern limits the possibility to uniquely determine its contribution to ITH. In this review, we first describe the major epigenetic mechanisms involved in tumourigenesis and then discuss how single-cell-based approaches contribute to dissecting the key role of epigenetic changes in tumour heterogeneity. Furthermore, we highlight the importance of dissecting the interplay between genetics, epigenetics, and tumour microenvironments to decipher the molecular mechanisms governing tumour progression and drug resistance.

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