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Quantitative analyses of structure-function heterogeneity of individual mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplastic transformation

ABSTRACT: Quantitative analyses of structure-function heterogeneity of individual mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplastic transformation

PROVIDER: PRJNA1205721 | ENA |

REPOSITORIES: ENA

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Quantitative analyses of structure-function heterogeneity of individual mitochondrial components reveal an early role of small-mitochondrial-networks in priming neoplastic transformation

Project description:We elucidate a biological mechanism of cancer initiation involving stem cell specification. Based on data from experimentation with a model carcinogen, we propose that conversion of large ‘Hyperfused Mitochondrial Networks’ (HMNs) to heterogenous ‘Small Mitochondrial Networks’ (SMNs) primes non-transformed cells towards stem cell driven neoplasticity. Mechanistically, the SMNs, enriched by modulation of the physical nodes and edges of mitochondrial networks, tunes the mitochondrial redox balance to establish transcriptomic interactions required to maintain a stem cell state to support neoplastic transformation.

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Fine-tuned repression of Drp1 driven mitochondrial fission primes a ‘stem/progenitor-like state’ to accelerate neoplastic transformation

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Fine-tuned repression of Drp1 driven mitochondrial fission primes a ‘stem/progenitor-like state’ to accelerate neoplastic transformation

Project description:Fine-tuned repression of Drp1 driven mitochondrial fission primes a ‘stem/progenitor-like state’ to accelerate neoplastic transformation

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Microenvironment-dependent proliferation and mitochondrial priming loss in mantle cell lymphoma is overcome by anti-CD20

Project description:Mantle cell lymphoma (MCL) accumulates in lymphoid organs but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support proliferation of MCL cells. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (IGF-1, BAFF, IL-6, IL-10). Of interest, we showed that our model recapitulated the MCL in situ molecular signatures i.e., proliferation, NFkB and survival signatures. We further demonstrated that proliferating MCL harbored an imbalance in Bcl-2 family expression leading to a consequent loss of mitochondrial priming. Interestingly, this loss of priming was overcome by the Type II anti-CD20 antibody obinutuzumab, which counteracted Bcl-xL induction through NFkB inhibition. Finally, we showed that the mitochondrial priming directly correlated with the sensitivity toward venetoclax and alkylating drugs. By identifying the microenvironment as the major support for proliferation and drug resistance in MCL, our results highlight a selective approach to target the lymphoma niche.

2017-01-02 | GSE86322 | GEO

Susceptibility of neoplastic transformation of human dental pulp stem cells DPSC in hypoxia

Project description:Neoplastic transformation of DPSC cultured under Hypoxia versus normoxia. Molecular characterization of cell markers associated with tumorigenicity.

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Priming

Project description:Priming

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FoxK1/2 – New Components in Insulin Regulation of Cellular and Mitochondrial Metabolism

Project description:FoxK1/2 – New Components in Insulin Regulation of Cellular and Mitochondrial Metabolism

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Susceptibility of neoplastic transformation of human dental pulp stem cells DPSC in hypoxia

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PRC2 Inactivation Induces Primary Chemoresistance by Repressing Mitochondrial Apoptosis in T-ALL

Project description:The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. To fully exploit this finding, it will be important to understand the molecular genetic contexts responsible for the relative mitochondrial priming of chemotherapy-sensitive versus resistant cell populations. Here, we report that mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical samples from children with T-ALL treated on recent Dana-Farber Cancer Institute or Children’s Oncology Group clinical trials, we found that loss-of-function mutations in any of three core components of PRC2 (EZH2, EED or SUZ12) were associated with resistance to mitochondrial apoptosis. In human T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action, including dexamethasone, doxorubicin and vincristine. PRC2 loss induced apoptosis resistance via transcriptional upregulation of the LIM domain transcription factor CRIP2, and subsequent downstream upregulation of the mitochondrial chaperone TRAP1. Importantly, TRAP1 overexpression was necessary to induce resistance to chemotherapy-induced apoptosis downstream of PRC2 inactivation, and pharmacologic inhibition of TRAP1 synergized with dexamethasone and doxorubicin. These findings demonstrate the importance of relative mitochondrial apoptotic priming as a prognostic factor in T-ALL, and implicate mitochondrial chaperone function as a molecular determinant of response to cancer chemotherapy, suggesting a rationale for targeted therapeutic intervention.

2018-10-18 | GSE112147 | GEO

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