Tracing back primed resistance in cancer via sister cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE223003 | GEO | 2023/12/22
REPOSITORIES: GEO
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Project description:B cell chronic lymphocytic leukemia - A model with immune response
Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3,
1.
Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India
2.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
3.
Department of Mathematics, Pomona College, Claremont, CA, 91711, United States
Abstract
B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based.
Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.
2020-01-09 | MODEL2001090002 | BioModels
Project description:Pluripotent stem cells provide a platform to interrogate control elements that function to generate all cell types of the body. Despite their utility for modeling development and disease, the relationship of mouse and human pluripotent stem cell states to one another remains largely undefined. We have shown that mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) are distinct, pluripotent states isolated from pre- and post-implantation embryos respectively. Human ES cells are different than mouse ES cells and share defining features with EpiSCs, yet are derived from pre-implantation human embryos. Here we show that EpiSCs can be routinely derived from pre-implantation mouse embryos. The pre-implantation-derived EpiSCs exhibit molecular features and functional properties consistent with bona fide EpiSCs. These results provide a simple method for isolating EpiSCs and offer direct insight into the intrinsic and extrinsic mechanisms that regulate the acquisition of distinct pluripotent states. 6 total samples were analyzed. Three pluripotent cell types (mES cells, E3.5 EpiSCs, and E5.5 EpiSCs) were compared with and without treatment of SB431542 for 4 days.
2011-01-25 | E-GEOD-26814 | biostudies-arrayexpress
Project description:NK cells contribute to protective anti-tumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis identified major differences in the transcriptional programs of tumor-infiltrating compared to circulating NK cells. Tumor-infiltrating NK cells represented seven clusters with distinct gene expression programs indicative of significant functional specialization, including cytotoxicity and chemokine synthesis programs. In particular, NK cells from three clusters expressed high levels of XCL1 and XCL2, which encode two chemokines known to recruit XCR1+ cross-presenting dendritic cells into tumors. In contrast, NK cells from two other clusters showed a higher level of expression of cytotoxicity genes. These data reveal key features of NK cells in human tumors and identify NK cell populations with specialized gene expression programs.
2019-10-23 | GSE139249 | GEO
Project description:Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrated that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and ‘memory’ NK cells possess distinct chromatin accessibility states, and that their epigenetic profiles reveal a ‘poised’ regulatory program at the memory stage. Furthermore, we elucidate how individual STAT proteins differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8+ T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8+ T cells. Overall, our study reveals the dynamic nature of epigenetic imprinting during the generation of innate and adaptive lymphocyte memory.
2018-05-29 | GSE108051 | GEO
Project description:Pluripotent stem cells provide a platform to interrogate control elements that function to generate all cell types of the body. Despite their utility for modeling development and disease, the relationship of mouse and human pluripotent stem cell states to one another remains largely undefined. We have shown that mouse embryonic stem (ES) cells and epiblast stem cells (EpiSCs) are distinct, pluripotent states isolated from pre- and post-implantation embryos respectively. Human ES cells are different than mouse ES cells and share defining features with EpiSCs, yet are derived from pre-implantation human embryos. Here we show that EpiSCs can be routinely derived from pre-implantation mouse embryos. The pre-implantation-derived EpiSCs exhibit molecular features and functional properties consistent with bona fide EpiSCs. These results provide a simple method for isolating EpiSCs and offer direct insight into the intrinsic and extrinsic mechanisms that regulate the acquisition of distinct pluripotent states.
2011-01-25 | GSE26814 | GEO
Project description:The cell lineage origin of interferon-producing killer dendritic cells (IKDC), which exhibit prominent anti-tumoral activity, has been subject to debate. Although IKDC were first described as a cell type exhibiting both pDC and NK cell properties, the current view reflects that IKDC merely represent activated NK cells expressing B220, which were thus renamed B220+ NK cells. Herein, we further investigate the lineage relationship of B220+ NK cells with regards to other NK cell subsets. We surprisingly find that, upon adoptive transfer, B220- NK cells did not acquire B220 expression, even in the presence of potent activating stimuli. These findings strongly argue against the concept that B220+ NK cells are activated NK cells in vivo. Moreover, we unequivocally demonstrate that B220+ NK cells are highly proliferative and differentiate into mature NK cells upon in vivo adoptive transfer. Additional phenotypic, functional and transcriptional characterizations further define B220+ NK cells as immediate precursors to mature NK cells. By analogy to pre-B cells and pre-DC, we propose that B220+ NK cells should be renamed pre-NK cells. The characterization of these novel attributes to pre-NK cells will guide the identification of their ortholog in humans, contributing to the design of potent cancer immunotherapies. Total RNA from B220+ NK cells compared to total RNA from CD27- and CD27+ NK cell subsets all isolated ex vivo from the spleen of B6.Rag-/-. Triplicatas were analysed.
2012-05-14 | E-GEOD-34237 | biostudies-arrayexpress
Project description:Our study investigates the features and anti-tumor function of extracellular vesicles (EVs) isolated from our well described NK cell line - NK3.3 - the only published clonal, normal human cell line to date. Natural killer (NK) cells, critical for proper immune function, destroy tumor cells primarily through the release of granules containing potent cytolytic molecules. NK cells also release these molecules within membrane-bound exosomes and microvesicles collectively known as EVs. We show that NK3.3 EVs contain the cytolytic molecules perforin, granzymes A and B, and granulysin, and an array of common EV proteins. We previously showed that the E3 ubiquitin ligase identified by our laboratory, natural killer lytic-associated molecule (NKLAM/RNF19b), is localized to NK granules and is essential for maximal NK killing; our current study shows NKLAM situated within the NK3.3 EV membrane. We demonstrate that treatment of an array of hematopoietic and non-hematopoietic tumor cell lines with NK3.3 EVs inhibits proliferation and induces apoptosis and cell death while leaving normal cells unaffected. The anti-tumor effects of NK3.3EVs were evaluated via proteomic analysis of K562 leukemia cells treated with NK3.3-derived EVs compared to treatment with non-cytotoxic HEK293 cell-derived EVs or PBS. The results of this analysis suggest strong inhibitory regulation of cell cycle- and cell survival-associated proteins. Taken together, our study suggests that NK3.3 EVs have the potential to be effective immunotherapeutic agents.
2021-09-07 | PXD027221 | Pride
Project description:Drug resistance (DR) is a phenomenon characterized by the tolerance of a disease to pharmaceutical treatment. In cancer patients, DR is one of the main challenges that limit the therapeutic potential of the existing treatments. Therefore, overcoming DR by restoring the sensitivity of cancer cells would be greatly beneficial. In this context, mathematical modeling can be used to provide novel therapeutic strategies that maximize the efficiency of anti-cancer agents and potentially overcome DR. In this paper, we present a new multiscale model devoted to the interaction of potential treatments with multiple myeloma (MM) development. In this model, MM cells are represented as individual objects that move, divide, and die by apoptosis. The fate of each cell depends on intracellular and extracellular regulation, as well as the administered treatment. The model is used to explore the combined effects of a tyrosine-kinase inhibitor (TKI) with a pentose phosphate pathway (PPP) inhibitor. We use numerical simulations to tailor effective and safe treatment regimens that may eradicate the MM tumors. The model suggests that an interval for the daily dose of the PPP inhibitor can maximize the responsiveness of MM cells to the treatment with TKIs. Then, it demonstrates that the combination of high-dose pulsatile TKI treatment with high-dose daily PPP inhibitor therapy can potentially eradicate the tumor.The predictions of numerical simulations using such a model can be considered as testable hypotheses in future pre-clinical experiments and clinical studies.
2020-01-09 | MODEL1912170004 | BioModels
Project description:We explored a novel hydrogel spheroid-based microfluidic model for screening lymphoma treatments. We utilized primary patient DLBCL cells in combination with NK cells and rCHOP treatment, and used ranscriptomic sequencing to determine the biological relevance of this approach. Our results showed complex changes in the transcriptomic response to treatment stimuli, including numerous metabolic and immunogenic changes. These findings support this model as an optimal platform for comparative screening of novel treatments.
2023-08-21 | GSE240989 | GEO
Project description:Our study investigates the features and anti-tumor function of extracellular vesicles (EVs) isolated from our well described NK cell line - NK3.3 - the only published clonal, normal human cell line to date. Natural killer (NK) cells, critical for proper immune function, destroy tumor cells primarily through the release of granules containing potent cytolytic molecules. NK cells also release these molecules within membrane-bound exosomes and microvesicles collectively known as EVs. We show that NK3.3 EVs contain the cytolytic molecules perforin, granzymes A and B, and granulysin, and an array of common EV proteins. We previously showed that the E3 ubiquitin ligase identified by our laboratory, natural killer lytic-associated molecule (NKLAM/RNF19b), is localized to NK granules and is essential for maximal NK killing; our current study shows NKLAM situated within the NK3.3 EV membrane. Analysis of NK3.3 EV contents also identified multiple RNA species including miRNAs associated with anti-tumor activity. We demonstrate that treatment of an array of hematopoietic and non-hematopoietic tumor cell lines with NK3.3 EVs inhibits proliferation and induces apoptosis and cell death while leaving normal cells unaffected. Taken together, our study suggests that NK3.3 EVs have the potential to be effective immunotherapeutic agents.
2021-09-07 | PXD027051 | Pride