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In vivo growth of subclones derived from Lewis lung carcinoma is determined by the tumor microenvironment not intrinsic proliferative ability

ABSTRACT: Heterogeneity is a fundamental feature of human tumors and plays a major role in drug resistance and disease progression. In the present study, we selected single-cell-derived cell lines (SCDCLs) derived from Lewis lung carcinoma (LLC1) cells to investigate tumorigenesis and heterogeneity. SCDCLs were generated using limiting dilution. Five SCDCLs were subcutaneously injected into wild-type C57BL/6N mice; however, they displayed significant differences in tumor growth. Subclone SCC1 grew the fastest in vivo, whereas it grew slower in vitro. The growth pattern of SCC2 was the opposite to that of SCC1. Genetic differences in these two subclones showed marked differences in cell adhesion and proliferation. Pathway enrichment results indicate that signal transduction and immune system responses were the most significantly altered functional categories in SCC2 cells compared to SCC1 cells in vitro. The number and activation of CD3+ and CD8+ T cells and NK cells in the tumor tissue of tumor-bearing mice inoculated with SCC2 were significantly higher, whereas those of myeloid cells were significantly lower, than those in the SCC1 and LLC1 groups. Our results suggest that the in vivo growth of two subclones derived from LLC1 was determined by the tumor microenvironment rather than their intrinsic proliferative cell characteristics.

ORGANISM(S): Mus musculus

PROVIDER: GSE216396 | GEO | 2023/10/23

REPOSITORIES: GEO

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Structural evidence for Scc4-dependent localization of cohesin loading

Project description:Purpose: The Goal of this study is to look at 1) Differences in genome wide localization of Scc2 between wild type and scc4-m35 cells in S-phase 2) Differences in genome wide localisation of Scc1 cohesin between wild type and scc4-m35 in metaphase arrested cells. Method: 1) Wild-type (AM15307) and scc4-m35 (AM15311) cells carrying SCC2-3FLAG were fixed for 2 hr, 15 min following an a-factor arrest. Samples were harvested, anti-HA ChIP was performed and both input and IP samples were sequenced for both strains. 2) Wild-type (AM1145), wild type constructed in the same way as the mutant strain (carrying a HIS3 marker) (AM15540) and scc4-m35 mutant (AM15537) cells carrying SCC1-6HA were synchronised with a-factor and arrested in mitosis by treatment with nocodazole/benomyl for 2 hr. Samples were harvested, anti-HA ChIP was performed and input and IP samples were sequenced for the three strains. Results: 1) This experiment did not yield meaningful data. 2) All 16 centromeres were specifically depleted of Scc1 in the scc4-m35 background. Scc1 depletion extended roughly 10 kilobases to either side of the core centromere but not to chromosome arms 1) ChIP-seq for S. cerevisiae Scc2-3FLAG in S-phase cells in Wild type and in scc4-m35 mutant (samples VM1-VM4). 2) ChIP-seq for Scc1-6HA in metaphase-arrested cells in Wild type and in scc4-m35 mutant (samples VM5-VM10) Vasso Makrantoni: experiments and Alastair Kerr: ChIP Seq Data analysis https://github.com/AlastairKerr/Hinshaw2015

2015-06-05 | E-GEOD-68573 | biostudies-arrayexpress

Scc2 Is a Potent Activator of Cohesin's ATPase that Promotes Loading by Binding Scc1 without Pds5

Project description:In addition to sharing with condensin an ability to organize DNA into chromatids, cohesin regulates enhancer-promoter interactions and confers sister chromatid cohesion. Association with chromosomes is regulated by hook-shaped HEAT repeat proteins that Associate With its Kleisin (Scc1) subunit (HAWKs), namely Scc3, Pds5, and Scc2. Unlike Pds5, Scc2 is not a stable cohesin constituent but, as shown here, transiently displaces Pds5 during loading. Scc1 mutations that compromise its interaction with Scc2 adversely affect cohesin’s ATPase activity, loading, and translocation while Scc2 mutations that alter how the ATPase responds to DNA abolish loading despite cohesin’s initial association with loading sites. Lastly, Scc2 mutations that permit loading in the absence of Scc4 increase Scc2’s association with chromosomal cohesin and reduce that of Pds5. We suggest that cohesin switches between two states, one with Pds5 bound to Scc1 that is not able to hydrolyse ATP efficiently but is capable of release from chromosomes and another in which Scc2, transiently replacing Pds5, stimulates the ATP hydrolysis necessary for loading and translocation away from loading sites.

2018-07-17 | GSE106182 | GEO

Scc2 counteracts a Wapl-independent mechanism that releases cohesin from chromosomes during G1

Project description:Cohesin’s association with chromosomes is determined by loading dependent on the Scc2/4 complex and release due to Wapl. We show here that Scc2 also actively maintains cohesin on chromosomes during G1. It does so by blocking a Wapl-independent release reaction that requires opening the cohesin ring at its Smc3/Scc1 interface as well as the D loop of Smc1’s ATPase. The Wapl-independent release mechanism is switched off as cells activate Cdk1 and enter G2/M and cannot be turned back on without cohesin’s dissociation from chromosomes. The latter phenomenon enabled us to show that in the absence of release mechanisms, cohesin rings that have already captured DNA in a Scc2-dependent manner before replication no longer require Scc2 to capture sister DNAs during S phase.

2019-06-06 | GSE132221 | GEO

Releasing activity disengages cohesin’s Smc3/Scc1 interface in a process blocked by acetylation

Project description:Sister chromatid cohesion conferred by entrapment of sister DNAs within a tripartite ring formed between cohesin’s Scc1, Smc1, and Smc3 subunits is generated during S and eventually destroyed at anaphase through cleavage of Scc1 by separase. Throughout the cell cycle, cohesin’s association with chromosomes is controlled by opposing activities: loading by the Scc2/4 complex and release by a separase independent releasing activity. Co-entrapment of sister DNAs during replication is accompanied by acetylation of Smc3 by Eco1, which blocks releasing activity and ensures that sisters remain stably connected. Because fusion of Smc3 to Scc1 prevents release and bypasses the requirement for Eco1, we suggested that release is mediated by disengagement of the Smc3/Scc1 interface. We now show that all mutations capable of bypassing Eco1, be they in cohesin’s Smc1, Smc3, Scc1,Wapl, Pds5, or Scc3 subunits, greatly reduce dissociation of N-terminal cleavage fragments of Scc1 (NScc1) from Smc3. We show that this process involves interaction between Smc ATPase heads and is inhibited by Smc3 acetylation

2016-02-18 | GSE76890 | GEO

Inactivation of the Budding Yeast Cohesin Loader Scc2 alters Gene Expression both Globally and in Response to a Single DNA Double Strand Break [ChIP-seq]

Project description:Genome integrity is fundamental for cell survival and cell cycle progression. Important mechanisms for keeping the genome intact are proper sister chromatid segregation, correct gene regulation and efficient repair of damaged DNA. Cohesin and its DNA loader, the Scc2/4 complex have been implicated in all these cellular actions. The gene regulation role has been described in several organisms. In yeast it has been suggested that the proteins in the cohesin network would effect transcription based on its role as insulator. More recently, data are emerging indicating direct roles for gene regulation also in yeast. Here we extend these studies by investigating whether the cohesin loader Scc2 is involved in regulation of gene expression. We performed global gene expression profiling in the absence and presence of DNA damage, in wild type and Scc2 deficient G2/M arrested cells, when it is known that Scc2 is important for DNA double strand break repair and formation of damage induced cohesion. We found that not only the DNA damage specific transcriptional response is distorted after inactivation of Scc2, but also the overall transcription profile. Interestingly, these alterations did not correlate with changes in cohesin binding. We investigated Scc1 FLAG tagged binding in WT ans Scc2-4 mutant in absence and presence of a single DNA DSB on Chr. VI

2014-10-21 | E-GEOD-62493 | biostudies-arrayexpress

Releasing activity disengages cohesinâs Smc3/Scc1 interface in a process blocked by acetylation

Project description:Sister chromatid cohesion conferred by entrapment of sister DNAs within a tripartite ring formed between cohesinâs Scc1, Smc1, and Smc3 subunits is generated during S and eventually destroyed at anaphase through cleavage of Scc1 by separase. Throughout the cell cycle, cohesinâs association with chromosomes is controlled by opposing activities: loading by the Scc2/4 complex and release by a separase independent releasing activity. Co-entrapment of sister DNAs during replication is accompanied by acetylation of Smc3 by Eco1, which blocks releasing activity and ensures that sisters remain stably connected. Because fusion of Smc3 to Scc1 prevents release and bypasses the requirement for Eco1, we suggested that release is mediated by disengagement of the Smc3/Scc1 interface. We now show that all mutations capable of bypassing Eco1, be they in cohesinâs Smc1, Smc3, Scc1,Wapl, Pds5, or Scc3 subunits, greatly reduce dissociation of N-terminal cleavage fragments of Scc1 (NScc1) from Smc3. We show that this process involves interaction between Smc ATPase heads and is inhibited by Smc3 acetylation Effect of mutations QQ and EQ in Smc3 on cohesin loading onto chromosomes

2016-02-18 | E-GEOD-76890 | biostudies-arrayexpress

PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma [mouse]

Project description:Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wildtype tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.

2022-06-18 | GSE206003 | GEO

PRC2 Heterogeneity Drives Tumor Growth in Medulloblastoma [Human]

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2019-12-01 | GSE128930 | GEO

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2022-05-25 | GSE201193 | GEO

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