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A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

ABSTRACT: Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Brain Cancer

SUBMITTER: Tobias Kessker

LAB HEAD: Wolfgang Wick

PROVIDER: PXD044001 | Pride | 2023-11-27

REPOSITORIES: Pride

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			Action	DRS
	CHI3L1OE-metadata-SDRF.tsv	Tabular
	Phospho_STY_Sites.txt	Txt
	oecf1-211029-DH3139-pC18-57.raw	Raw
	oecf1-211029-DH3139-pC18-59.raw	Raw
	oecf1-211029-DH3139-pC18-60.raw	Raw

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A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

Project description:Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patientsÃ¢Â€Â™ prognosis, and serves as a robust prognostic biomarker.

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UBE2D3 facilitates NHEJ by orchestrating ATM signalling through multi-level control of RNF168

Project description:Maintenance of genome integrity requires tight control of DNA damage signalling and repair activities at DNA lesions, as well as their restriction at telomeres. Key components of the mechanisms underlying appropriate responses to DNA damage include phosphorylation events by DNA damage response (DDR) kinases, as well as regulatory and proteolytic ubiquitination events by the ubiquitin machinery. How these events are coordinated and controlled in a concerted manner to achieve productive DNA repair is not well understood. Here we identify the ubiquitin-conjugating enzyme UBE2D3 (or UBCH5C) as a critical multi-level regulator of ATM kinase-induced DDR signalling that controls the activity of the ubiquitin-ligase RNF168 to promote non-homologous end-joining (NHEJ) mediated DNA repair at telomeres. We find that UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both of which are mediated by RNF168 upon DNA damage-induced ATM activation. In addition, we find that UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated KAP1-S824 phosphorylation, important for heterochromatic DNA repair. Mechanistically, we show that defective KAP1-S824 phosphorylation upon UBE2D3-deficiency is linked to RNF168 hyperaccumulation and caused by aberrant PP2A phosphatase activity, the counteraction of which restores both KAP1-S824 phosphorylation and telomeric NHEJ in UBE2D3-deficient cells. Our results identify UBE2D3 as a novel multi-level regulator of NHEJ that orchestrates the activities of RNF168 in DNA repair. Moreover, we reveal the existence of a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and PP2A-mediated restriction of ATM-dependent KAP1 phosphorylation.

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Human melanoma MeWo cell phosphopeptide enriched Orbitrap MS

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