Biology subjects

Sakhteman, A.

Publications and source records attributed to Sakhteman, A..

7 recordsLinked to original sources

bioRxiv2026

TOPAS: phosphoproteome data analysis and decision support platform for molecular tumor boards

The molecular tumor board (MTB) is central to precision oncology, providing personalized treatment recommendations based on molecular profiles of patient tumors. Genomics is instrumental for MTBs but often fails to identify clinically actionable targets, a gap that phosphoproteomics can fill. We present the tumor proteome activity status (TOPAS) platform, an end-to-end analysis pipeline that converts terabytes of phosphoproteomic data into patient-specific reports for MTB discussions, focusing on clinically relevant signaling linked to oncogenic mechanisms and therapeutic targets. Designed to scale with growing cohorts, the platform integrates data from 1,998 tumor samples to support patient- and cohort-level hypothesis generation. A web portal handles quality control, calculates TOPAS scores, identifies tumor antigens and immune checkpoints, and offers interactive analyses of differential protein abundance and outlier detection. The TOPAS platform is open source, addresses a critical unmet need and facilitates broader adoption of phosphoproteomics in precision oncology in the future.

bioinformatics↗

bioRxiv2026

Prospective pan-cancer phosphoproteomics at clinical scale extends therapeutic options in precision oncology

Genomics-guided precision oncology has improved survival in cancer entities with actionable mutations but cannot capture oncogenic signaling that manifests at the protein level. Here, we report a prospective, real-world pan-cancer study profiling proteomes and phosphoproteomes of 1,998 tumor samples from adults and children with rare or advanced cancers enrolled in the German precision oncology programs DKFZ/NCT/DKTK MASTER, CATCH and INFORM and their molecular tumor boards (MTBs). We developed tumor proteome activity status (TOPAS) scores for 46 clinically relevant kinases, an immune activity score capturing antigen presentation and T-cell activation and identified therapeutically targetable cell-surface proteins for 94% of patients. These readouts enhance MTB recommendations by exposing actionable non-genomic kinase activity, refining interpretation of oncogenic genome alterations, and highlighting cell-surface treatment options. Three proof-of-concept analyses indicate clinical utility including kinase activity-stratified pazopanib response in sarcoma, immune activity score-tracked checkpoint-inhibitor outcomes pan-cancer, and a phosphoproteomic biomarker distinguishing EGFR-inhibitor response in chordoma.

cancer biology↗

bioRxiv2026

Proteogenomics of Blumeria hordei supports RNA and protein coding innovative potential derived from transposable elements

Some filamentous plant-pathogenic fungi have comparably large genome sizes within the fungal kingdom due to the proliferation of transposable elements (TEs). Blumeria hordei (Bh), the causal agent of the powdery mildew disease on barley, is a filamentous obligate biotrophic fungus. Compared to other ascomycetes, it contains a low number of genes but a high genomic TE content of approximately 75%. Yet, a comprehensive understanding of the contribution of TEs to the RNA and protein landscape of Bh is lacking. Here, we use Bh as a model to study transcripts and proteins derived from genes and individual TEs. Therefore, we created two high-quality genome assemblies of the German Bh isolate TUM1 and the Australian Bh isolate AUS1. We applied deep proteomics with mass spectrometry, long-read and short-read sequencing on both DNA and RNA. Based on these multi-omic resources, we completed nearly gapless genome assemblies, new gene and TE annotations, and effector predictions. Using long-read RNA sequencing, we detected extensive co-transcription of TEs and genes as TE-gene chimeric transcripts. We identified previously unpredicted splice variants or genes, partially supported by proteomics. The intergenic and TE genomic space of Bh TUM1 gives rise to thousands of transcripts and several novel TE-derived proteins that lack from previous TE protein predictions. Together, this supports an existing potential for expression of novel transcripts and proteins from highly abundant TEs in the Bh genome.

plant biology↗

bioRxiv2025

Illuminating oncogenic KRAS signaling by multi-dimensional chemical proteomics

Mutated KRAS is among the most frequent activating genetic alterations in cancer and drug discovery efforts have led to inhibitors that block its activity. To better understand oncogenic KRAS signaling and the cytostatic effects of drugs, we performed comprehensive dose-dependent proteome-wide target deconvolution, pathway engagement and protein expression characterization of KRAS, MEK, ERK, SHP2 and SOS1 inhibitors in pancreatic (KRAS G12C, G12D) and lung cancer (KRAS G12C) cells. Analysis of the resulting 687,954 dose-response curves available online revealed both common and cell line-specific signaling networks dominated by oncogenic KRAS activity. Time-dose experiments separated early KRAS-MEK-ERK from CDK-mediated signaling that cause cells to exit from the cell cycle. This transition to a quiescent state occurred without substantial proteome re-modelling but extensive changes of protein phosphorylation and ubiquitylation. The collective data highlights the complexity of KRAS signaling in cancer and places a large number of new proteins into this functional context.

cell biology↗

bioRxiv2024

Gemcitabine and ATR inhibitors synergize to kill PDAC cells by blocking DNA damage response

The DNA-damaging agent gemcitabine (GEM) is a first-line treatment for pancreatic cancer but chemoresistance is frequently observed. Several clinical trials investigate the efficacy of GEM in combination with targeted drugs including kinase inhibitors but the experimental evidence for such rational is often unclear. Here, we phenotypically screened 13 human pancreatic adenocarcinoma (PDAC) cell lines against GEM in combination with 140 clinical kinase inhibitors and observed strong synergy for the ATR inhibitor Elimusertib in most cell lines. Dose-dependent phosphoproteome profiling of four ATR inhibitors following DNA damage induction by GEM revealed a strong block of the DNA damage response pathway including phosphorylated pS468 of CHEK1 as the underlying mechanism of drug synergy. The current work provides a strong rationale for why the combination of GEM and ATR inhibition may be useful for the treatment of PDAC patients and constitutes a rich phenotypic and molecular resource for further investigating effective drug combinations.

cancer biology↗

bioRxiv2023

Correlation of myeloid-derived suppressor cell expansion with upregulated transposable elements in severe COVID-19 unveiled in single-cell RNA sequencing reanalysis

Some studies investigated the potential role of transposable elements (TEs) in COVID-19 pathogenesis and complications. However, to the best of our knowledge, there is no study to examine the possible association of TEs expression in cell functions and its potential role in COVID-19 immune response at the single-cell level. In this study, we reanalyzed single-cell RNA seq data of bronchoalveolar lavage (BAL) samples obtained from six severe COVID-19 patients and three healthy donors to assess the probable correlation of TE expression with the immune responses induced by the SARS-CoV-2 virus in COVID-19 patients. Our findings indicated that the expansion of myeloid-derived suppressor cells (MDSCs) may be a characteristic feature of COVID-19. Additionally, a significant increase in TEs expression in MDSCs was observed. This upregulation of TEs in COVID-19 may be linked to the adaptability of these cells in response to their microenvironments. Furthermore, it appears that the identification of overexpressed TEs by Pattern recognition receptors (PRRs) in MDSCs may enhance the suppressive capacity of these cells. Thus, this study emphasizes the crucial role of TEs in the functionality of MDSCs during COVID-19.

systems biology↗

bioRxiv2023

A region-resolved proteomic map of the human brain enabled by high-throughput proteomics

Substantial efforts are underway that aim to deepen our understanding of human brain morphology, structure and function using high-resolution imaging as well has high-content molecular profiling technologies. The current work adds to these efforts by providing a comprehensive and quantitative protein expression map of 13 anatomically distinct brain regions covering more than 10,000 proteins. This was enabled by the optimization, characterization and implementation of a high-sensitivity and high-throughput micro-flow liquid chromatography timsTOF tandem mass spectrometry system (LC-MS/MS) capable of analyzing >2,000 consecutive samples prepared from formalin fixed paraffin embedded (FFPE) material. Analysis of this proteomic resource highlighted e.g. brain region-enriched protein expression patterns and functional protein classes, protein localization differences between brain regions and individual protein markers for specific brain regions. To facilitate access to and ease further mining of the data by the scientific community, all data can be explored online in a purpose-built Shiny App (https://brain-region-atlas.proteomics.ls.tum.de).

neuroscience↗