Molecular Mechanisms of Pituitary Cell Plasticity

Blood malignancies often arise from undifferentiated hematopoietic stem cells or partially differentiated stem-like cells. A tight balance of multipotency and differentiation, cell division, and quiescence underlying normal hematopoiesis requires a special program governed by the transcriptional machinery. Acquisition of drug resistance by tumor cells also involves reprogramming of their transcriptional landscape. Limiting tumor cell plasticity by disabling reprogramming of the gene transcription is a promising strategy for improvement of treatment outcomes. Herein, we review the molecular mechanisms of action of transcription-targeted drugs in hematological malignancies (largely in leukemia) with particular respect to the results of clinical trials.

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Molecular Mechanisms Involved in Schwann Cell Plasticity

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2017.00038 ◽

2017 ◽

Vol 10 ◽

Cited By ~ 56

Author(s):

Angélique Boerboom ◽

Valérie Dion ◽

Alain Chariot ◽

Rachelle Franzen

Keyword(s):

Schwann Cell ◽

Molecular Mechanisms ◽

Cell Plasticity

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Application of Single-Cell Multi-Omics in Dissecting Cancer Cell Plasticity and Tumor Heterogeneity

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.757024 ◽

2021 ◽

Vol 8 ◽

Author(s):

Deshen Pan ◽

Deshui Jia

Keyword(s):

Single Cell ◽

Cancer Cell ◽

Tumor Heterogeneity ◽

Recent Progress ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Tumor Development ◽

Cell Plasticity ◽

Translational Cancer Research ◽

Cellular Components

Tumor heterogeneity, a hallmark of cancer, impairs the efficacy of cancer therapy and drives tumor progression. Exploring inter- and intra-tumoral heterogeneity not only provides insights into tumor development and progression, but also guides the design of personalized therapies. Previously, high-throughput sequencing techniques have been used to investigate the heterogeneity of tumor ecosystems. However, they could not provide a high-resolution landscape of cellular components in tumor ecosystem. Recently, advance in single-cell technologies has provided an unprecedented resolution to uncover the intra-tumoral heterogeneity by profiling the transcriptomes, genomes, proteomes and epigenomes of the cellular components and also their spatial distribution, which greatly accelerated the process of basic and translational cancer research. Importantly, it has been demonstrated that some cancer cells are able to transit between different states in order to adapt to the changing tumor microenvironment, which led to increased cellular plasticity and tumor heterogeneity. Understanding the molecular mechanisms driving cancer cell plasticity is critical for developing precision therapies. In this review, we summarize the recent progress in dissecting the cancer cell plasticity and tumor heterogeneity by use of single-cell multi-omics techniques.

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The Eye as a Transplantation Site to Monitor Pancreatic Islet Cell Plasticity

Frontiers in Endocrinology ◽

10.3389/fendo.2021.652853 ◽

2021 ◽

Vol 12 ◽

Author(s):

Erwin Ilegems ◽

Per-Olof Berggren

Keyword(s):

Beta Cells ◽

Pancreatic Islet ◽

Islet Cell ◽

Molecular Mechanisms ◽

Cell Function ◽

Severe Disease ◽

Cell Mass ◽

Beta Cell Mass ◽

Cell Plasticity ◽

Pancreatic Islet Cell

The endocrine cells confined in the islets of Langerhans are responsible for the maintenance of blood glucose homeostasis. In particular, beta cells produce and secrete insulin, an essential hormone regulating glucose uptake and metabolism. An insufficient amount of beta cells or defects in the molecular mechanisms leading to glucose-induced insulin secretion trigger the development of diabetes, a severe disease with epidemic spreading throughout the world. A comprehensive appreciation of the diverse adaptive procedures regulating beta cell mass and function is thus of paramount importance for the understanding of diabetes pathogenesis and for the development of effective therapeutic strategies. While significant findings were obtained by the use of islets isolated from the pancreas, in vitro studies are inherently limited since they lack the many factors influencing pancreatic islet cell function in vivo and do not allow for longitudinal monitoring of islet cell plasticity in the living organism. In this respect a number of imaging methodologies have been developed over the years for the study of islets in situ in the pancreas, a challenging task due to the relatively small size of the islets and their location, scattered throughout the organ. To increase imaging resolution and allow for longitudinal studies in individual islets, another strategy is based on the transplantation of islets into other sites that are more accessible for imaging. In this review we present the anterior chamber of the eye as a transplantation and imaging site for the study of pancreatic islet cell plasticity, and summarize the major research outcomes facilitated by this technological platform.

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Cancer Stem Cell Plasticity – A Deadly Deal

10.20944/preprints201912.0388.v1 ◽

2019 ◽

Author(s):

P. T. Archana ◽

Saxena Kritika ◽

Reshma Murali ◽

Mohit Kumar Jolly ◽

Radhika Nair

Keyword(s):

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Therapeutic Resistance ◽

Extensive Investigation ◽

Epigenetic Factors ◽

Therapeutic Approaches ◽

Cell Plasticity ◽

Mesenchymal Transition ◽

Recent Developments ◽

High Level

Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. The molecular mechanisms underlying such plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment. In this review, we discuss the recent developments in understanding CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity with implications in improving existing therapeutic approaches.

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MicroRNA-222 Regulates Melanoma Plasticity

Journal of Clinical Medicine ◽

10.3390/jcm9082573 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2573

Author(s):

Maria Chiara Lionetti ◽

Filippo Cola ◽

Oleksandr Chepizhko ◽

Maria Rita Fumagalli ◽

Francesc Font-Clos ◽

...

Keyword(s):

Mathematical Model ◽

Stem Cell ◽

Cancer Stem Cell ◽

Molecular Mechanisms ◽

Human Melanoma ◽

The Other ◽

Phenotypic Switching ◽

Cell Subpopulation ◽

Cell Plasticity ◽

Key Factor

Melanoma is one of the most aggressive and highly resistant tumors. Cell plasticity in melanoma is one of the main culprits behind its metastatic capabilities. The detailed molecular mechanisms controlling melanoma plasticity are still not completely understood. Here we combine mathematical models of phenotypic switching with experiments on IgR39 human melanoma cells to identify possible key targets to impair phenotypic switching. Our mathematical model shows that a cancer stem cell subpopulation within the tumor prevents phenotypic switching of the other cancer cells. Experiments reveal that hsa-mir-222 is a key factor enabling this process. Our results shed new light on melanoma plasticity, providing a potential target and guidance for therapeutic studies.

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An Intricate Connection between Alternative Splicing and Phenotypic Plasticity in Development and Cancer

Cells ◽

10.3390/cells9010034 ◽

2019 ◽

Vol 9 (1) ◽

pp. 34 ◽

Cited By ~ 4

Author(s):

Giuseppe Biamonti ◽

Lucia Infantino ◽

Daniela Gaglio ◽

Angela Amato

Keyword(s):

Alternative Splicing ◽

Cancer Cells ◽

Cancer Cell ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

Dependent Manner ◽

Cellular Plasticity ◽

Cell Plasticity ◽

Cellular Mechanisms

During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue- and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment.

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Male sex chromosomal complement exacerbates the pathogenicity of Th17 cells in a chronic model of CNS autoimmunity

10.1101/640904 ◽

2019 ◽

Author(s):

Prenitha Mercy Ignatius Arokia Doss ◽

Joanie Baillargeon ◽

Asmita Pradeep Yeola ◽

John B. Williams ◽

Mickael Leclercq ◽

...

Keyword(s):

Th17 Cells ◽

Molecular Mechanisms ◽

Transfer Model ◽

Disease Course ◽

Cell Plasticity ◽

Chromosomal Complement ◽

Chronic Model ◽

Cns Autoimmunity ◽

Male Sex ◽

Cell Adoptive Transfer

SummarySex differences in the incidence and severity of multiple sclerosis (MS) have long been recognized. However, the underlying cellular and molecular mechanisms for why male sex is associated with more aggressive and debilitating disease remain poorly defined. Using an T cell adoptive transfer model of chronic EAE, we find that male Th17 cells induced disease of increased severity relative to female Th17 cells, irrespective of whether transferred to male or female recipients. Throughout the disease course, a greater frequency of male Th17 cells produced the heterodox cytokine IFNγ, a hallmark of pathogenic Th17 responses. Intriguingly, sex chromosomal complement, and not hormones, were responsible for the increased pathogenicity of male Th17 cells and an X-linked immune regulator, Jarid1c, was downregulated in both pathogenic male Th17 and CD4+ T cells from men with MS. Together, our data indicate that male sex critical regulates Th17 cell plasticity and pathogenicity via sex chromosomal complement.

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FSH secretion predominates in vivo and in vitro in patients with non-functioning pituitary adenomas

Acta Endocrinologica ◽

10.1530/eje.1.01854 ◽

2005 ◽

Vol 152 (3) ◽

pp. 363-370 ◽

Cited By ~ 8

Author(s):

P L Hanson ◽

S J B Aylwin ◽

J P Monson ◽

J M Burrin

Keyword(s):

Cell Cultures ◽

Pituitary Adenomas ◽

Molecular Mechanisms ◽

Pituitary Tumour ◽

Pituitary Cell ◽

Pituitary Cells ◽

Functional Studies ◽

Non Functioning Pituitary Adenomas

Objective: Non-functioning pituitary adenomas (NFPAs) are characterised by the lack of symptoms of hormone hypersecretory syndromes but in vitro studies have demonstrated that tumour cells may stain for gonadotrophins and/or their α- or β-subunits. In this study, we aimed to examine the pattern of secretion of LH and FSH from a series of pituitary adenomas cultured in vitro and where data were available to relate the results to pre-operative serum gonadotrophin levels. Methods: The in vitro secretion of LH and FSH was measured from 46 cultured NFPAs and compared with pre-operative serum gonadotrophin levels in 38 patients. Peritumorous ‘normal’ pituitary cell cultures from 20 additional pituitary tumour patients were used for comparison with the NFPA group. Results: A median pre-operative LH:FSH ratio of 0.33:1 was found in 38 patients with NFPAs. Preferential secretion of FSH was also documented from media of 46 NFPAs cultured in vitro with a median LH:FSH ratio of 0.32:1. A significant correlation (r = 0.43, P < 0.01) was observed between serum and media levels of FSH but not LH. Peritumorous ‘normal’ pituitary cells released LH and FSH in a reversed ratio (median LH:FSH ratio = 3.6:1, P < 0.01 compared with NFPAs). Conclusions: This study has evaluated pre-operative serum gonadotrophin levels and in vitro release of hormones in cultures of surgically removed tissue from patients with NFPAs. The data suggest preferential secretion of FSH occurs both in vitro and in vivo. By demonstrating that NFPAs cultured in vitro reflect the in vivo situation of preferential secretion of FSH, it may be possible in future to perform functional studies using this system to elucidate the cellular and molecular mechanisms involved in the development of an imbalance in gonadotroph cells preferentially overproducing FSH in NFPAs.

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Research models and mesenchymal/epithelial plasticity of osteosarcoma

Cell & Bioscience ◽

10.1186/s13578-021-00600-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Xiaobin Yu ◽

Jason T. Yustein ◽

Jianming Xu

Keyword(s):

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Young Patients ◽

Cell Plasticity ◽

Human Patient ◽

Mesenchymal Transition ◽

Abnormal Growth ◽

Epithelial Plasticity ◽

Canine Models ◽

Surviving Rate

AbstractMost osteosarcomas (OSs) develop from mesenchymal cells at the bone with abnormal growth in young patients. OS has an annual incidence of 3.4 per million people and a 60–70% 5-year surviving rate. About 20% of OS patients have metastasis at diagnosis, and only 27% of patients with metastatic OS survive longer than 5 years. Mutation of tumor suppressors RB1, TP53, REQL4 and INK4a and/or deregulation of PI3K/mTOR, TGFβ, RANKL/NF-κB and IGF pathways have been linked to OS development. However, the agents targeting these pathways have yielded disappointing clinical outcomes. Surgery and chemotherapy remain the main treatments of OS. Recurrent and metastatic OSs are commonly resistant to these therapies. Spontaneous canine models, carcinogen-induced rodent models, transgenic mouse models, human patient-derived xenograft models, and cell lines from animal and human OSs have been developed for studying the initiation, growth and progression of OS and testing candidate drugs of OS. The cell plasticity regulated by epithelial-to-mesenchymal transition transcription factors (EMT-TFs) such as TWIST1, SNAIL, SLUG, ZEB1 and ZEB2 plays an important role in maintenance of the mesenchymal status and promotion of cell invasion and metastasis of OS cells. Multiple microRNAs including miR-30/9/23b/29c/194/200, proteins including SYT-SSX1/2 fusion proteins and OVOL2, and other factors that inhibit AMF/PGI and LRP5 can suppress either the expression or activity of EMT-TFs to increase epithelial features and inhibit OS metastasis. Further understanding of the molecular mechanisms that regulate OS cell plasticity should provide potential targets and therapeutic strategies for improving OS treatment.

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