scholarly journals Tolerant/Persister Cancer Cells and the Path to Resistance to Targeted Therapy

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2601
Author(s):  
Mirna Swayden ◽  
Houssein Chhouri ◽  
Youssef Anouar ◽  
Luca Grumolato
Keyword(s):  
Chromatin Remodeling ◽  
Targeted Therapies ◽  
Feedback Loops ◽  
Special Focus ◽  
Cancer Resistance ◽  
Persister Cells ◽  
Negative Feedback Loops ◽  
Genetic Mechanisms ◽  
Transcriptional Rewiring

The capacity of cancer to adapt to treatment and evolve is a major limitation for targeted therapies. While the role of new acquired mutations is well-established, recent findings indicate that resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of these cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine/paracrine communication among tumor cells and within the tumor microenvironment. In this review, we discuss the non-genetic mechanisms that eventually result in cancer resistance to targeted therapies, with a special focus on those involving changes in gene expression.

scholarly journals MAPK modulation of yeast pheromone signaling output and the role of phosphorylation sites in the scaffold protein Ste5

2019 ◽  
Vol 30 (8) ◽  
pp. 1037-1049 ◽  
Author(s):  
Matthew J. Winters ◽  
Peter M. Pryciak
Keyword(s):  
Negative Feedback ◽  
Scaffold Protein ◽  
Feedback Loops ◽  
Phosphorylation Sites ◽  
Pheromone Response ◽  
Pheromone Response Pathway ◽  
Negative Feedback Loops ◽  
Pheromone Signaling ◽  
Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) mediate numerous eukaryotic signaling responses. They also can modulate their own signaling output via positive or negative feedback loops. In the yeast pheromone response pathway, the MAPK Fus3 triggers negative feedback that dampens its own activity. One target of this feedback is Ste5, a scaffold protein that promotes Fus3 activation. Binding of Fus3 to a docking motif (D motif) in Ste5 causes signal dampening, which was proposed to involve a central cluster of phosphorylation sites in Ste5. Here, we reanalyzed the role of these central sites. Contrary to prior claims, phosphorylation-mimicking mutations at these sites did not impair signaling. Also, the hyperactive signaling previously observed when these sites were mutated to nonphosphorylatable residues arose from their replacement with valine residues and was not observed with other substitutes. Instead, a cluster of N-terminal sites in Ste5, not the central sites, is required for the rapid dampening of initial responses. Further results suggest that the role of the Fus3 D motif is most simply explained by a tethering effect that promotes Ste5 phosphorylation, rather than an allosteric effect proposed to regulate Fus3 activity. These findings substantially revise our understanding of how MAPK feedback attenuates scaffold-mediated signaling in this model pathway.

scholarly journals The Role of Extracellular Vesicles in Mediating Resistance to Anticancer Therapies

2021 ◽  
Vol 22 (8) ◽  
pp. 4166
Author(s):  
Saeideh Maleki ◽  
James Jabalee ◽  
Cathie Garnis
Keyword(s):  
Drug Resistance ◽  
Extracellular Vesicles ◽  
Targeted Therapies ◽  
Genetic Material ◽  
Cell Communication ◽  
Genetic Alterations ◽  
Damage Repair ◽  
Genetic Mechanisms ◽  
Lipid Bilayer Vesicles

Although advances in targeted therapies have driven great progress in cancer treatment and outcomes, drug resistance remains a major obstacle to improving patient survival. Several mechanisms are involved in developing resistance to both conventional chemotherapy and molecularly targeted therapies, including drug efflux, secondary mutations, compensatory genetic alterations occurring upstream or downstream of a drug target, oncogenic bypass, drug activation and inactivation, and DNA damage repair. Extracellular vesicles (EVs) are membrane-bound lipid bilayer vesicles that are involved in cell–cell communication and regulating biological processes. EVs derived from cancer cells play critical roles in tumor progression, metastasis, and drug resistance by delivering protein and genetic material to cells of the tumor microenvironment. Understanding the biochemical and genetic mechanisms underlying drug resistance will aid in the development of new therapeutic strategies. Herein, we review the role of EVs as mediators of drug resistance in the context of cancer.

scholarly journals Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 915
Author(s):  
Wout Devlies ◽  
Florian Handle ◽  
Gaëtan Devos ◽  
Steven Joniau ◽  
Frank Claessens
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Targeted Therapies ◽  
Treatment Strategies ◽  
Resistance Mechanisms ◽  
Cancer Therapies ◽  
Cancer Resistance ◽  
Tumor Resistance ◽  
Preclinical Models

Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer.

FAITH–BASED COMMUNITIES AND POLITICS IN DULLSTROOM-EMNOTWENI: LOCAL STORIES OF IDENTITY

2016 ◽  
Vol 1 (1) ◽  
pp. 45-57 ◽  
Author(s):  
Christina Landman
Keyword(s):  
Higher Education ◽  
Service Delivery ◽  
Special Focus ◽  
Traditional Role ◽  
Cultural Conflicts ◽  
Local Identities ◽  
Political Interests ◽  
Local Municipality ◽  
The Face

A majority of the black community of Dullstroom-Emnotweni in the Mpumalanga highveld in the east of South Africa trace their descent back to the southern Ndebele of the so-called ‘Mapoch Gronden’, who lost their land in the 1880s to become farm workers on their own land. A hundred years later, in 1980, descendants of the ‘Mapoggers’ settled in the newly built ‘township’ of Dullstroom, called Sakhelwe, finding jobs on the railways or as domestic workers. Oral interviews with the inhabitants of Sakhelwe – a name eventually abandoned in favour of Dullstroom- Emnotweni – testify to histories of transition from landowner to farmworker to unskilled labourer. The stories also highlight cultural conflicts between people of Ndebele, Pedi and Swazi descent and the influence of decades of subordination on local identities. Research projects conducted in this and the wider area of the eMakhazeni Local Municipality reveal the struggle to maintain religious, gender and youth identities in the face of competing political interests. Service delivery, higher education, space for women and the role of faith-based organisations in particular seem to be sites of contestation. Churches and their role in development and transformation, where they compete with political parties and state institutions, are the special focus of this study. They attempt to remain free from party politics, but are nevertheless co-opted into contra-culturing the lack of service delivery, poor standards of higher education and inadequate space for women, which are outside their traditional role of sustaining an oppressed community.

Tumor suppressor role of chromatin-remodeling factor ARID1A

2013 ◽  
Vol 35 (3) ◽  
pp. 255-261 ◽  
Author(s):  
Xiao-Qiang GUO ◽  
Qiao-Xia ZHANG ◽  
Wei-Ren HUANG ◽  
Xiang-Lin DUAN ◽  
Zhi-Ming CAI
Keyword(s):  
Tumor Suppressor ◽  
Chromatin Remodeling

Can the Lewis basicity of an isolated solvent molecule be used for characterizing solvent effects?

2020 ◽  
Vol 16 ◽  
Author(s):  
Jean-François Gal ◽  
Pierre-Charles Maria
Keyword(s):  
Solvent Effects ◽  
Molecular Level ◽  
Solvent Molecule ◽  
Lewis Base ◽  
Bulk Liquid ◽  
Donor Number ◽  
Special Focus ◽  
Solution Processes ◽  
Inert Solvent

Background: The ubiquitous Lewis acid/base interactions are important in solution processes. Analytical chemistry may benefit of a better understanding of the role of Lewis basicity, at the molecular level or acting through a bulk solvent effect. Objective: To clearly delineate (i) the basicity at a molecular level, hereafter referred as solute basicity, and (ii) the solvent basicity, which is a bulk-liquid property. Method: The literature that relates Lewis basicity scales and solvent effects is analyzed. A special focus is placed on two extensive scales, the Donor Number, DN, and the BF3 affinity scale, BF3A, which were obtained by calorimetric measurement on molecules as solutes diluted in a quasi-inert solvent, and therefore define a molecular Lewis basicity. We discuss the validity of these solute scales when regarded as solvent scales, in particular when the basicity of strongly associated liquids is discussed. Results: We demonstrate the drawbacks of confusing the Lewis basicity of a solvent molecule, isolated as solute, and that of the bulk liquid solvent itself. Conclusion: Consequently, we recommend a reasoned use of the concept of Lewis basicity taking clearly into account the specificity of the process for which a Lewis basicity effect may be invoked. In particular, the action of the Lewis base, either as an isolated entity, or as a bulk liquid, must be distinguished.

scholarly journals Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 78-90
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Brain Cell ◽  
Special Focus ◽  
Molecular Alterations ◽  
Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

scholarly journals The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoping Xu ◽  
Kai Ni ◽  
Yafeng He ◽  
Jianke Ren ◽  
Chongkui Sun ◽  
...  
Keyword(s):  
Chromatin Remodeling ◽  
Critical Role ◽  
Genomic Stability ◽  
Dna Degradation ◽  
Replication Forks ◽  
Filament Formation ◽  
Epigenetic Regulator ◽  
Centromeric Instability ◽  
Stalled Replication Forks

AbstractThe Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is caused by mutations in LSH/HELLS, a chromatin remodeler promoting incorporation of histone variant macroH2A. Here, we demonstrate that LSH depletion results in degradation of nascent DNA at stalled replication forks and the generation of genomic instability. The protection of stalled forks is mediated by macroH2A, whose knockdown mimics LSH depletion and whose overexpression rescues nascent DNA degradation. LSH or macroH2A deficiency leads to an impairment of RAD51 loading, a factor that prevents MRE11 and EXO1 mediated nascent DNA degradation. The defect in RAD51 loading is linked to a disbalance of BRCA1 and 53BP1 accumulation at stalled forks. This is associated with perturbed histone modifications, including abnormal H4K20 methylation that is critical for BRCA1 enrichment and 53BP1 exclusion. Altogether, our results illuminate the mechanism underlying a human syndrome and reveal a critical role of LSH mediated chromatin remodeling in genomic stability.

scholarly journals 26.A. Workshop: Assessing the role of policies and actions to address childhood obesity

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
◽  
Keyword(s):  
Public Health ◽  
Childhood Obesity ◽  
Stakeholder Engagement ◽  
Special Focus ◽  
Policy Options ◽  
Sustainable Solutions ◽  
Relevant Evidence ◽  
Multi Stakeholder ◽  
The Impact

Abstract   Childhood obesity has grown to become one of the most dramatic features of the global obesity epidemic, with long-term consequences. The spread of obesity has been fueled by changes in social norms and living environments that have shaped individual behaviours making them conducive to excessive and imbalanced nutrition, sedentary lifestyles, and ultimately obesity and associated diseases. The STOP project will aim to generate scientifically sound, novel and policy-relevant evidence on the factors that have contributed to the spread of childhood obesity in European countries and on the effects of alternative technological and organisational solutions and policy options available to address the problem. STOP will translate the evidence gathered and generated into indicators and measurements, policy briefs and toolkits and multi-stakeholder frameworks. A special focus of STOP is understanding the stakeholders' networks and drivers of stakeholders' action. STOP will establish new ways for policy-relevant evidence to be generated, made available and used in the design and implementation of effective and sustainable solutions for childhood obesity at the EU, national and local levels. Each of the policy work packages will: Produce evidence syntheses and impact simulations for different policy approaches;Assess selected policy approaches and actions in children cohorts and other relevant settings;Devise policy toolkits and policy guidance to support the adoption and implementation of specific actions by relevant actors;Establish a country-based European accountability and monitoring framework in each policy area. The workshop aims to: Showcase the impact of different policy options evaluated throughout the STOP project;Increase participants' understanding and awareness of the opportunities and challenges associated with the implementation of selected policies;Increase awareness of public health professionals of the importance of overcoming siloes in identifying and implementing public health policies;Increase the understanding of multi-stakeholder engagement. The discussion will explore the role of stakeholders across different policy areas. We will explore the different definitions of “stakeholders” and “multi-stakeholders” engagement. This will also be an opportunity to explore some of the benefits, risks and challenges around stakeholder engagement, and explore what are the different types of stakeholders involved in these policies as well as their roles. The workshop will offer an opportunity to: Inform participants about existing physical activity, regulatory and fiscal policies to address childhood obesity;Inform participants about new, innovative EU-level projects that aim to address childhood obesity;Outline preliminary findings of the STOP project with regards to the effectiveness of the evaluated policies;Identify some of the gaps and limitations of existing policies and discuss some of the steps to ensure successful policy implementation. Key messages Present new evidence on what policy approaches work in addressing key determinants of childhood obesity. Showcase findings on the attitudes of different stakeholders towards obesity policies, and debate the benefits, risks and challenges of multi-stakeholder engagement.

scholarly journals Osteoarthritis: Insights Offered by the Study of Bone Mass Genetics

2021 ◽  
Vol 19 (2) ◽  
pp. 115-122
Author(s):  
A. Hartley ◽  
C. L. Gregson ◽  
L. Paternoster ◽  
J. H. Tobias
Keyword(s):  
Bone Mass ◽  
Causal Effect ◽  
Mendelian Randomisation ◽  
Mineral Density ◽  
High Bone Mass ◽  
Increased Risk ◽  
High Bone ◽  
Genetic Mechanisms ◽  
Additional Support

Abstract Purpose of Review This paper reviews how bone genetics has contributed to our understanding of the pathogenesis of osteoarthritis. As well as identifying specific genetic mechanisms involved in osteoporosis which also contribute to osteoarthritis, we review whether bone mineral density (BMD) plays a causal role in OA development. Recent Findings We examined whether those genetically predisposed to elevated BMD are at increased risk of developing OA, using our high bone mass (HBM) cohort. HBM individuals were found to have a greater prevalence of OA compared with family controls and greater development of radiographic features of OA over 8 years, with predominantly osteophytic OA. Initial Mendelian randomisation analysis provided additional support for a causal effect of increased BMD on increased OA risk. In contrast, more recent investigation estimates this relationship to be bi-directional. However, both these findings could be explained instead by shared biological pathways. Summary Pathways which contribute to BMD appear to play an important role in OA development, likely reflecting shared common mechanisms as opposed to a causal effect of raised BMD on OA. Studies in HBM individuals suggest this reflects an important role of mechanisms involved in bone formation in OA development; however further work is required to establish whether the same applies to more common forms of OA within the general population.

Sign in / Sign up

Export Citation Format

Share Document