Biology subjects

Zirngibl, K.

Publications and source records attributed to Zirngibl, K..

3 recordsLinked to original sources

bioRxiv2023

Integration of Thermal Proteome Profiling with phosphoproteomic and transcriptomic data via mechanistic network models decodes the molecular response to PARP inhibition

The deregulation of complex diseases often spans multiple molecular processes. A multimodal functional characterization of these processes can shed light on the disease mechanisms and the effect of drugs. Thermal Proteome Profiling (TPP) is a mass-spectrometry based technique assessing changes in thermal protein stability that can serve as proxies of functional changes of the proteome. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a framework for causal integration of multi-omics, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover known mechanistic consequences of PARP inhibition in ovarian cancer cells on cell cycle and DNA damage response in detail and to uncover new insights into drug response mechanisms related to interferon and hippo signaling. We found that TPP complements the other omics data and allowed us to obtain a network model with higher coverage of the main underlying mechanisms. These results illustrate the added value of TPP, and more generally the power of network models to integrate the information provided by different omics technologies. We anticipate that this strategy can be used to broadly integrate functional proteomics with other omics to study complex molecular processes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=63 SRC="FIGDIR/small/553354v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@af952eorg.highwire.dtl.DTLVardef@16b1d1borg.highwire.dtl.DTLVardef@1440787org.highwire.dtl.DTLVardef@14a4227_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2020

Oncogenic memory underlying minimal residual disease in breast cancer

Tumor relapse is responsible for most breast cancer related deaths1,2. The disease recurrence stems from treatment refractory cancer cells that persist as minimal residual disease (MRD) for years following initial therapy3. Yet, the molecular characteristics defining the malignancy of MRD remain elusive due to difficulties in observing these rare cells in patients or in model organisms. Here, we use a tractable organoid system and multi-omics analysis to show that the dormant MRD cells retain metabolic peculiarities reminiscent of the tumor state. While the MRD cells were distinct from both normal and tumor cells at a global transcriptomic level, their metabolomic and lipidomic profile markedly resembled that of the tumor state. The MRD cells particularly exhibited a de-regulated urea cycle and elevated glycolysis. We find the latter being crucial for their survival and could be selectively targeted using a small molecule inhibitor of glycolytic activity. We validated these metabolic peculiarities of the MRD cells in corresponding tissues obtained from the mouse model as well as in transcriptomic data from patients following neo-adjuvant therapy. Together, our results show that the treatment surviving MRD cells retain features of the tumor state over an extended period suggestive of an oncogenic memory. In accord, we found striking similarity in DNA methylation profiles between the tumor and the MRD cells. The distinction of MRD from normal breast cells comes as a surprise, considering their phenotypic similarity with regards to proliferation and polarized epithelial organization. The metabolic aberrances of the MRD cells offer a therapeutic opportunity towards tackling emergence of breast tumor recurrence in post-treatment care.

cancer biology↗

bioRxiv2018

Single-cell transcriptomics identifies CD44 as a new marker and regulator of haematopoietic stem cells development

The endothelial to haematopoietic transition (EHT) is the process whereby haemogenic endothelium differentiates into haematopoietic stem and progenitor cells (HSPCs). The intermediary steps of this process are unclear, in particular the identity of endothelial cells that give rise to HSPCs is unknown. Using single-cell transcriptome analysis and antibody screening we identified CD44 as a new marker of EHT enabling us to isolate robustly the different stages of EHT in the aorta gonad mesonephros (AGM) region. This allowed us to provide a very detailed phenotypical and transcriptional profile for haemogenic endothelial cells, characterising them with high expression of genes related to Notch signalling, TGFbeta/BMP antagonists (Smad6, Smad7 and Bmper) and a downregulation of genes related to glycolysis and the TCA cycle. Moreover, we demonstrated that by inhibiting the interaction between CD44 and its ligand hyaluronan we could block EHT, identifying a new regulator of HSPC development.

developmental biology↗