Time-course transcriptomic profiling of cell-cycle entry in MCF10A cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE173509 | GEO | 2021/04/29
REPOSITORIES: GEO
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Project description:Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) lead to cell-cycle arrest but also trigger T cell-mediated immunity, which might be mediated by the qualitative and quantitative changes in human leukocyte antigen (HLA) ligands on the cancer cell surface. We investigated the effects of CDK4/6i, Abemaciclib and Palbociclib, on the immunopeptidome at subclinical, non-toxic, levels in breast cancer cell lines by biochemical isolation and identification of HLA ligands followed by network analyses. This treatment led to upregulation of cell surface HLA and revealed hundreds of induced HLA ligands in breast cancer cell lines. These new ligands were significantly enriched for peptides derived from proteins involved in the “G1/S phase transition of cell cycle” including HLA ligands from CDK4/6, Cyclin D1 and the 26S regulatory proteasomal subunit 4 (PSMC1). Interestingly, peptides from this essential biological process, that is targeted by Abemaciclib and Palbociclib, were predicted to be the most likely to induce a T cell response within the group of all induced HLA ligands when compared to HLA ligands from the DMSO-treated group. In strong contrast, peptides induced by solely one of the drugs had a lower T cell recognition score compared to the DMSO control suggesting that the observed effect is class dependent. This general hypothesis was exemplified by a peptide from PSMC1 which was among the HLA ligands with highest prediction scores and which elicited a T cell response in healthy donors. Overall, these data demonstrate that CDK4/6i treatment gives rise to drug-induced HLA ligands, that have the highest chance for being recognized by T cells if they are derived from the inhibited process of G1/S phase transition, thus providing evidence that inhibition of a distinct cellular process leads to increased presentation of the involved proteins that may be targeted by immunotherapeutic agents.
2021-09-10 | PXD024965 | Pride
Project description:Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain cancer without cure. DIPG has high percentage histone mutation at K27M on histone H3 locus, which is believed to be one of the drivers of the tumorigenesis. Dysregulation of G1/S cell cycle checkpoint is more enriched in the H3.3K27M mutant subgroup. In this study, we reported that palbociclib (PD0332991), a specific and cytostatic inhibitor of CDK4/6, effectively suppresses the growth of DIPG cells in vitro and in vivo. We established patient derived cell lines from treatment-naïve specimens, which all have H3.3K27M mutation. And our DIPG cell lines with H3.3K27M mutation have high CDK4/6 expression. Then, we showed that depletion of CDK4 or CDK6 inhibits DIPG cells growth and blocks G1/S transition. Furthermore, palbociclib effectively repressed all 8 cell lines self-renewal, proliferation and cell cycle progression from G1 to S phase in vitro. Transcriptome analysis showed that palbociclib not only blocks G1/S transition, it also blocks other oncogenic targets such as Myc. Finally, palbociclib activity was assayed in vivo against DIPG orthotropic xenografts to demonstrate the high efficiency of blocking tumor growth. Our findings revealed that palbociclib could be the therapy strategy for DIPG.
2019-06-20 | GSE115976 | GEO
Project description:Time-course transcriptomic profiling of cell-cycle entry in MCF10A cells
| PRJNA725870 | ENA
Project description:Proteomic and phosphoproteomic analysis of MCF7 cells treated with Palbociclib (CDK4/6 inhibitor), PF3600 (CDK2 inhibitor) or both for 1 hour and 24 hours.
'P_1_1'
P refers to phosphoproteomic analysis. Otherwise, global proteomics was performed.
Number (1,2,3) refers to the run number. 3 runs were performed. Samples were TMT labelled and in each run there were the following samples:
DMSO 1 h, DMSO 24 h, 1uM Palbociclib 25nM PF3600 1 h, 1uM Palbociclib 25nM PF3600 24 h, 1uM Palbociclib 1 h, 1uM Palbociclib 24 h, 25nM PF3600 1 h, 25nM PF3600 24 h.
Number (1-24 for P or 1-12 for global) refers to the fraction.
2023-05-03 | MSV000091849 | MassIVE
Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.
2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress
Project description:Palbociclib (Ibrance, Pfizer) is a recent drug approved by the FDA for phase 3 clinical trials in treating estrogen-receptor-positive and HER2-negative breast cancer. In vitro, palbociclib, a selective inhibitor of CDK4 and CDK6, was shown to reduce cellular proliferation of breast cancer cell lines by blocking progression of cells from G1 into S phase of the cell cycle. While the primary targets of palbociclib have been deciphered, the molecular mechanisms leading to drug resistance as well as off-targets effects of palbociclib are not known. To identify new palbociclib targets we propose a quantitative mass spectrometry and a Cellular Thermal Shift Assay (CETSA) that works under the assumption that protein-drug interaction stabilises the protein thus, leading to an increase in thermostability
2018-04-18 | PXD003704 | Pride
Project description:normal breast cell line MCF10A were treated with TSA or vehicle (DMSO) for 4 hours
2012-11-30 | E-MTAB-667 | biostudies-arrayexpress
Project description:By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. Induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell cycle phases. S-phase synchronization upon removal of the early-G1 block (pG1-S) fails to completely restore scheduled gene expression. Consequently, coordinate loss of IRF4 and gain of Bim and Noxa expression sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 and more profoundly in pG1-S in vitro. Induction of pG1 and pG1-S by CDK4/CDK6 inhibition augments tumor-specific bortezomib killing in myeloma xenografts. Inhibition of CDK4/CDK6 in combination therapy thus represents a novel mechanism-based cancer therapy. PD 0332991 (PD) is the only known specific and reversible CDK4/CDK6 inhibitor. Gene expression was measured in myeloma MM1.S cells treated with PD (0.25 uM) in triplicate for 12, 24 or 36 h, or in cells released from G1, induced by 24hPD, for 4 or 18 h.
2012-04-06 | E-GEOD-35728 | biostudies-arrayexpress
Project description:MCF10A were either untreated, treated with torin or by starvation, to induce autophagy. RNA sequencing and ribosome profiling was performed.
2016-02-17 | GSE59816 | GEO
Project description:CDK4/6 inhibitors are used in the treatment of advanced estrogen receptor (ER)(+) breast cancer (BC). Their efficacy in ER(-) and early stage BC is currently under investigation. Here, we show that palbociclib, a CDK4/6 inhibitor, can inhibit both progression of ductal carcinoma in situ (DCIS) and growth of invasive disease in both an ER(-) basal BC model (MCFDCIS) and an ER(+) luminal model (MCF7 intraductal injection). In MCFDCIS cells palbociclib repressed cell cycle gene expression, inhibited proliferation, induced senescence and normalized tumorspheres formed in Matrigel whilst the formation of acini by normal mammary epithelial cells (MCF10A) was not affected. Palbociclib treatment of mice with MCFDCIS tumors inhibited their malignant progression and reduced proliferation of invasive lesions. Transcriptomic analysis of the tumor and stromal cell compartments showed that cell cycle and senescence genes, and MUC16, an ovarian cancer biomarker gene, were repressed during treatment. Knockdown of MUC16 in MCFDCIS cells inhibited proliferation of invasive lesions but not progression of DCIS. After cessation of palbociclib treatment genes associated with differentiation, e.g. p63, inflammation, IFNγ response and antigen processing and presentation remained suppressed in the tumor and surrounding stroma. We conclude that palbociclib can prevent progression of DCIS and is anti-proliferative in ER(-) invasive disease mediated in part via MUC16. Lasting effects of CDK4/6 inhibition after drug withdrawal on differentiation and the immune response could impact the approach to treatment of early stage ER(-) breast cancer.
2019-08-30 | GSE130903 | GEO