Biology subjects

Wicki, A.

Publications and source records attributed to Wicki, A..

5 recordsLinked to original sources

bioRxiv2025

Isolation of functional supramolecular attack particles (SMAPs)

High density cultures of the GMP compatible NK-92 natural killer cell line release heterogeneous extracellular particles (EP), notably extracellular vesicles (EV) and non-vesicular extracellular particles (NVEP). The NVEP include a small proportion of supramolecular attack particles (SMAPs), the direct cytotoxic potential of which suggests therapeutic promise, yet scalable enrichment and functional evaluation alongside other extracellular particles (EPs) have been lacking. Here, we develop a high-resolution serial size-exclusion liquid chromatography (SELC) workflow that resolves EPs into 4 fractions F1-F4, in which EV are enriched in F2 and SMAPs are enriched in F3. Multi-modal characterization using Nanoparticle Tracking Analysis (NTA), Nano Flow Cytometry (Nano FCM), Transmission Electron Microscopy (TEM), Total Internal Reflection Microscopy (TIRFM) and Proteomics) demonstrated that F2 NK-92 EVs are [~]130-150 nm particles enriched for complement proteins, whereas SMAPs (F3) are 100-110 nm particles enriched for cytotoxic proteins (PRF1, GZMB) and SMAP shell components (e.g., THBS1, THBS4). Functionally, Ca2+-stabilized SMAPs (F3) trigger caspase-3-dependent apoptosis in tumor cell lines with robust dose responses, while F2 lacks direct cytotoxicity in vitro. Ex vivo, F3 SMAPs kill patient-derived breast cancer and chronic lymphocytic leukaemia cells (CLL) in a concentration-dependent manner. In NSG mice, intra-tumoral treatment with SMAPs (F3) restrains the growth of aggressive B16F10 melanoma and PANC-1 pancreatic cancer, confirming in vivo functionality. These results establish a scalable method to isolate and compare NK-derived particle classes and provide a foundation for targeted SMAP engineering as a promising approach for treatment of solid tumours. Significance StatementCell therapies face barriers in solid tumours, including lack of entry and suppression. NK cells release extracellular particles (EPs), including supramolecular attack particles (SMAPs), that can traffic into tumour tissue. We define a practical, scalable chromatography process that resolves NK-derived SMAPs from other EPs and demonstrate that SMAPs induce caspase mediated apoptosis in vitro and engage in cytotoxic lymphocyte independent anti-tumour activity in vivo. These insights open a route to engineering and testing SMAP-based therapeutics to overcome limitations of whole-cell approaches in solid cancers.

immunology↗

bioRxiv2025

RIPPLET: Mutation-Only Gene and Pathway Profiling for Precision Oncology

Clinical implementation of comprehensive genomic profiling, via whole-genome (WGS) or whole-exome sequencing (WES), is constrained by sparse mutation burdens and analytic pipelines reliant on matched transcriptomes. Currently, gene-centric analysis prevails, but overlooks the complex, multigene and pathway perturbations shaping tumor biology. We introduce RIPPLET, a DNA-only framework converting somatic variants into quantitative gene-impact scores and topology-aware pathway-perturbation profiles. By integrating tissue-specific protein-protein interaction networks with cohort-informed reweighting, RIPPLET prioritizes likely functionally relevant alterations. Applied across 33 TCGA cancer types, RIPPLET surpasses four state-of-the-art multi-omic driver-prioritization tools in recovering cancer type-specific drivers. In a cohort of metastatic cutaneous melanomas, it identifies pathway signatures that predict drug response, provide prognostic insight and distinguish immune-infiltration phenotypes without RNA data, independently validated on an in-house cohort. RIPPLET enables DNA-only inference of tumor-specific gene and pathway dysregulation, aligning with clinical sequencing workflows and offering a scalable precision-oncology strategy in transcriptome-limited settings.

bioinformatics↗

bioRxiv2025

SAUNA - Simulated Annealing for Unique Nucleosome Arrangements from Cell-Free DNA-Sequencing Data

WithdrawalThis preprint has been withdrawn by the authors. While the preprint cites the work by Schoepflin et al. (2013) (reference [20] in the preprint), it has been brought to the authors attention that the preprint may not appropriately acknowledge the extent to which their work depends on the work by Schoepflin et al. (2013). The authors apologize for this oversight and want to emphasize that they did not intend to misattribute the work of Schoepflin et al. (2013) and want to thank them for the code of NucPosSimulator which is a core component of SAUNAs algorithm. Therefore, the authors do not wish this work to be cited as reference for the project. For any questions, please contact the corresponding author.

bioinformatics↗

bioRxiv2024

Mapping the niche of breast cancer metastases in lung and liver

Breast cancer progression to visceral organs such as lung and liver is regarded as a dreadful event, unequivocally associated with a poor prognosis. Yet, these vital sites are characterized by highly diverse cellular microenvironments and physiological functions, suggesting that they may influence cancer cells behavior in divergent ways. Unexpectedly, we find that while the liver microenvironment fosters metastasis-promoting properties and boosts secondary spread, the lungs impose a roadblock to the same processes. Using patient data and tissues from rapid autopsy, as well as mouse models with barcode-mediated metastasis tracing, niche labeling technology and single cell analysis of both tumor cells and their direct microenvironment, we dissect cellular and molecular microenvironmental factors that impose this differential behavior. Among these, we identify BMP2-producing endothelial cells as critical players within the liver metastatic niche, capable to enhance metastasis-to-metastasis dissemination. Targeting BMP2 receptor on breast cancer cells suppresses their metastasis-forming ability. Altogether, we reveal a contrast in the site-specific behavior of lung and liver metastases in breast cancer, highlighting microenvironmental factors that contribute to this diversity, as well as organ-specific opportunities for intervention.

cancer biology↗

bioRxiv2023

Chemotherapy synergizes with cancer vaccines and expands stem-like TCF1+CD8+ T cells

Therapeutic cancer vaccines, whether based on neoantigens or shared antigens, will likely be given in the clinic together with the standard of care, which often comprises immune checkpoint blockade therapy and chemotherapy. It remains unclear, however, whether vaccines effectively synergize with chemotherapy. Here, we tested the combination of a heterologous prime-boost viral vector vaccine with chemotherapy (CarboTaxol) and anti-PD- 1. We show that this triple combination improves tumor control and survival in different murine tumor models. CarboTaxol, and also cyclophosphamide, acted as an immune adjuvant for the vaccines, enhancing tumor-specific CD8+ T-cell responses, irrespective of the presence of a tumor. These chemotherapies expanded stem-like T cell factor 1 (TCF1)+CD8+ T cells. Inhibition of the transcriptional activity of TCF1/{beta}-catenin with a small molecule inhibitor abolished the immune adjuvant effect of CarboTaxol. This study sheds light on the new immunomodulatory roles of chemotherapies and holds promises for clinical testing of this combination strategy. HighlightsO_LIThe combination of CarboTaxol with viral vector cancer vaccines and anti-PD-1 promotes better tumor control, tumor clearance, and survival C_LIO_LICarboTaxol increases TCF1 expression in CD8+ T cells and expands stem-like TCF1+CD8+ T cells C_LIO_LICarboTaxol acts as an adjuvant for cancer vaccines irrespective of the presence of a tumor and this effect is mediated by TCF1/{beta}-catenin activity C_LI

immunology↗