Biology subjects

Peitzsch, C.

Publications and source records attributed to Peitzsch, C..

4 recordsLinked to original sources

bioRxiv2024

Epigenome profiling identifies H3K27me3 regulation of extra-cellular matrix composition in human corticogenesis

Epigenetic mechanisms regulate gene expression programs during neurogenesis, but the extent of epigenetic remodelling during human cortical development remains unknown. Here, we characterize the epigenetic landscape of the human developing neocortex by leveraging Epi-CyTOF, a mass cytometry-based approach for the simultaneous single cell analysis of more than 30 epigenetic marks. We identify H3K27me3, deposited by Polycomb Repressive Complex 2 (PRC2), as the modification with the strongest cell type-specific enrichment. Inhibition of PRC2 in human cortical organoids resulted in a shift of neural progenitor cell (NPC) proliferation towards differentiation. Cell type- specific profiling of H3K27me3 not only identified neuronal differentiation genes in the human neocortex, but also extra-cellular matrix (ECM) genes. PRC2 inhibition resulted in increased production of the proteoglycan Syndecan 1. Overall, this study comprehensively characterizes the epigenetic state of specific neural cell types and highlights a novel role for H3K27me3 in regulating the ECM composition in the human developing neocortex.

developmental biology↗

bioRxiv2024

Blood-based detection of MMP11 as a marker of prostate cancer progression regulated by the ALDH1A1-TGF-β1 signaling mechanism

BackgroundProstate cancer (PCa) is the second most common type of tumor diagnosed in men and the fifth leading cause of cancer-related death in male patients. The response of metastatic disease to standard treatment is heterogeneous. As for now, there is no curative treatment option available for metastatic PCa, and the clinical tests capable of predicting metastatic dissemination and metastatic response to the therapies are lacking. Our recent study identifies aldehyde dehydrogenases ALDH1A1 and ALDH1A3 as critical regulators of PCa metastases. Still, the exact mechanisms mediating the role of these proteins in PCa metastatic dissemination remain not fully understood, and plasma-based biomarkers of these metastatic mechanisms are also not available. MethodsGenetic silencing, gene overexpression, or treatment with different doses of the retinoic acid (RA) isomers, which are the products of ALDH catalytic activity, were used to modulate the interplay between retinoic acid receptors (RARs) and androgen receptor (AR). RNA sequencing (RNAseq), reporter assays, and chromatin immunoprecipitation (ChIP) analysis were employed to validate the role of RARs and AR in the regulation of the transforming growth factor-beta 1 (TGFB1) expression. Gene expression levels of ALDH1A1, ALDH1A3, and the matrix metalloproteinase 11 (MMP11) and their correlation with pathological parameters and clinical outcomes were analyzed by mining several publicly available patient datasets as well as our multi-center transcriptomic dataset from patients with high-risk and locally advanced PCa. The levels of MMP11 protein were analyzed by enzyme-linked immunosorbent assay (ELISA) in independent cohorts of plasma samples from patients with localized or metastatic PCa and healthy donors, while plasma proteome profiles were obtained for selected subsets of PCa patients. ResultsWe could show that ALDH1A1 and ALDH1A3 genes differently regulate TGFB1 expression in a RAR-and AR-dependent manner. We further observed that the TGF-{beta}1 pathway contributes to the regulation of the MMPs, including MMP11. We have confirmed the relevance of MMP11 as a promising clinical marker for PCa using several independent gene expression datasets. Further, we have validated plasma MMP11 levels as a prognostic biomarker in patients with metastatic PCa. Finally, we proposed a hypothetical ALDH1A1/MMP11-related plasma proteome-based prognostic signature. ConclusionsTGFB1/MMP11 signaling contributes to the ALDH1A1-driven PCa metastases. MMP11 is a promising blood-based biomarker of PCa progression.

cancer biology↗

bioRxiv2021

GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.

cancer biology↗

bioRxiv2020

High complexity cellular barcoding and clonal tracing reveals stochastic and deterministic parameters of radiation resistance

The impact of functional heterogeneity in response to radiation therapy is poorly understood to the present. It remains elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. We applied high-resolution lentiviral cellular barcoding for quantitative clonal tracking and deconvolution of clonal dynamics in response to IR. Clonal tracking of over 400.000 HNSCC patient-derived tumor cells and the analyses of over 1500 million sequencing reads in clonogenic survival assays reveals that fractionated IR induced a strong selective pressure for clonal reduction. This significantly exceeded uniform clonal survival probabilities indicative for a strong clone-to clone difference within tumor cell lines. IR induced clonal reduction affected the majority of tumor cells ranging between 96-75% and correlated to the degree of radiation sensitivity. Survival and clonogenicity is characterized by an intensive clonal distortion and dominance of individual tumor cells. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. A 2-fold increase in radiation resistance results in a 4-fold (p<0.05) higher deterministic clonal selection showing that the ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype commonly surviving IR was found at a frequency of 0.6-3.3% (p<0.001, FDR 3%). With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for tracking dynamics of clonogenic survival in response to radiation. This enables the quantification of intrinsically radiation resistant tumor cells from patient samples and reveals the contribution of stochastic and deterministic clonal selection processes in response to IR.

systems biology↗