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Genome-wide expression profiling of human prostate stromal cells in response to multiple chemotherapeutic agents

ABSTRACT: The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in senescence associated secretory phenotype (SASP) and fuels advanced pathologies particularly cancer resistance. However, the complete mechanism underlying SASP development in the tumor microenvironment (TME) remains unclear. We treated PSC27, a primary normal human prostate stromal cell line, with two distinct groups of chemotherapeutic drugs that are either genotoxic or not, and determined the key molecules and their associated pathways responsible for development of a typical SASP phenotype under DNA damage conditions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE82033 | GEO | 2018/08/31

REPOSITORIES: GEO

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Genome-wide transcript profiling of human prostate stromal cells in response to genotoxic treatment and SASP inhibitors

Project description:Cancer develops in a complex environment that encompasses a wide spectrum of benign cell types, while the local microenvironment reduces the efficacy of multiple forms of cancer therapies. The DNA damage secretory program (DDSP) provoked by the side effects of genotoxic therapeutics results in cellular senescence and the senescence-associated secretory phenotype (SASP), the side effects of the latter frequently fueling advanced pathologies particularly therapeutic resistance. However, candidate approaches to prevent or circumvent the SASP development remains limited. We treated PSC27, a primary normal human prostate stromal cell line, with the genoxotic agents hereby represented by bleomycin, to investigate the relevant mechanisms. In order to control the SASP development, a group of potential SASP inhibitors were applied including p38MAPK, mTOR and TAK1 suppressors. The purpose was to compare the efficacy and effectiveness of these chemicals in combinatin with typical anticancer drugs in minimizing the secretory phenotype upon DNA damage that functionally remodels human stromal cells.

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Expression landscape of human stromal cells in preclinical trials involving chemotherapeutic and histone demethylase KDM4-targeting agents

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Project description:Rapid advancements in next generation sequencing (NGS) have revolutionized system-based analysis of genome-wide expression, cellular pathways and stress responses. We performed this cGAS-STING-associated study to streamline the transcriptomic profiling (RNA-seq) of human stromal cells manifesting a typical senescence-associated secretory phenotype (SASP) in a DNA damage setting.

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MLL1 is essential for the senescence-associated secretory phenotype

Project description:This SuperSeries is composed of the SubSeries listed below. Oncogene-induced senescence (OIS) and therapy-induced senescence (TIS), while tumor-suppressive, also promote procarcinogenic effects by activating the DNA damage response (DDR), which in turn induces inflammation. This inflammatory response prominently includes an array of cytokines known as the senescence-associated secretory phenotype (SASP). Previous observations link the transcription-associated methyltransferase and oncoprotein MLL1 to the DDR, leading us to investigate the role of MLL1 in SASP expression. Our findings reveal direct MLL1 epigenetic control over proproliferative cell cycle genes: MLL1 inhibition represses expression of proproliferative cell cycle regulators required for DNA replication and DDR activation, thus disabling SASP expression. Strikingly, however, these effects of MLL1 inhibition on SASP gene expression do not impair OIS and, furthermore, abolish the ability of the SASP to enhance cancer cell proliferation. More broadly, MLL1 inhibition also reduces âSASP-likeâ inflammatory gene expression from cancer cells in vitro and in vivo independently of senescence. Taken together, these data demonstrate that MLL1 inhibition may be a powerful and effective strategy for inducing cancerous growth arrest through the direct epigenetic regulation of proliferation-promoting genes and the avoidance of deleterious OIS- or TIS-related tumor secretomes, which can promote both drug resistance and tumor progression. Previously published samples GSM1135046, GSM1135044, GSM1135047, and GSM1135045 were also studied in this investigation and appear in GSE36641. This did not involve re-sequencing or re-alignment, nor any other deviation from the data protocols in that series. Refer to individual Series

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