Biology subjects

Wild, P.

Publications and source records attributed to Wild, P..

4 recordsLinked to original sources

bioRxiv2026

ProxiCapture Reveals Context-Dependent CRBN Interactore Landscape of Molecular Glue Degraders

Molecular glue degraders represent a rapidly expanding class of small molecules that reprogram E3 ubiquitin ligases to ubiquitinate and degrade disease-relevant proteins. Despite their therapeutic potential, the rational design of molecular glues remains challenging, underscoring the need for unbiased discovery strategies to identify new chemical targets. To address this challenge, we developed ProxiCapture, an affinity-based proteomics workflow that models the systemic behavior of molecular glues by combining purified CRBN-{Delta}HBD protein with native cell or tissue lysates. Systematic application of ProxiCapture across eight cancer cell lines, three maturation states of immune cells, and paired primary healthy and tumor tissues, revealed a comprehensive atlas of pomalidomide interactors, including previously uncharacterized targets. These findings reveal that degrader-dependent interactors of CRBN are context-dependent, requiring broad, physiologically and systemically anchored sampling to uncover the full "glueable" proteome. Taken together, this study establishes a scalable platform that accelerates molecular glue discovery by capturing cell- and tissue-specific recruitment profiles and predicting system-wide degrader effects.

cancer biology↗

bioRxiv2021

Single-Cell Proteomics Defines the Cellular Heterogeneity of Localized Prostate Cancer

Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. The aim of this study was to identify novel prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated immune cell infiltrates by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1,6 million cells from 58 men with localized prostate cancer. To perform this task, we proposed a novel computational pipeline, Franken, which showed unprecedented combination of performance, sensitivity and scalability for high dimensional clustering compared to state of the art methods. We were able to describe subpopulations of immune, stromal, and prostate cells, including unique changes occurring in tumor tissues and high grade disease providing insights into the coordinated progression of prostate cancer. Our results further indicated that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease, which were confirmed through imaging. Our methodology could be used to discover novel prognostic biomarkers to personalize treatment and improve outcomes.

cancer biology↗

bioRxiv2019

High-throughput proteomic analysis of FFPE tissue samples facilitates tumor stratification

Formalin-fixed, paraffin-embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here we developed a pressure cycling technology (PCT)-SWATH mass spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B-cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between one to 15 years in a biobank and show a high degree of the proteome pattern similarity between two types histological region of small FFPE samples, i.e. punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of certain degree of biological variations. Applying the method to two independent DLBCL cohorts we identified myeloperoxidase (MPO), a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered.

biochemistry↗

bioRxiv2018

Rapid proteotyping reveals cancer biology and drug response determinants in the NCI-60 cells

We describe the rapid and reproducible acquisition of quantitative proteome maps for the NCI-60 cancer cell lines and their use to reveal cancer biology and drug response determinants. Proteome datasets for the 60 cell lines were acquired in duplicate within 30 working days using pressure cycling technology and SWATH mass spectrometry. We consistently quantified 3,171 proteotypic proteins annotated in the SwissProt database across all cell lines, generating a data matrix with 0.1% missing values, allowing analyses of protein complexes and pathway activities across all the cancer cells. Systematic and integrative analysis of the genetic variation, mRNA expression and proteomic data of the NCI-60 cancer cell lines uncovered complementarity between different types of molecular data in the prediction of the response to 240 drugs. We additionally identified novel proteomic drug response determinants for clinically relevant chemotherapeutic and targeted therapies. We anticipate that this study represents a significant advance toward the translational application of proteotypes, which reveal biological insights that are easily missed in the absence of proteomic data.

systems biology↗