Swalduz, A. | Search bioRxiv

bioRxiv2024

Deep learning uncovers histological patterns of YAP1/TEAD activity related to disease aggressiveness in cancer patients.

Over the last decade, Hippo signaling has emerged as a major tumor-suppressing pathway. Its dysregulation is associated with abnormal expression of YAP1 and TEAD-family genes. Recent works have highlighted the role of YAP1/TEAD activity in several cancers and its potential therapeutic implications. Therefore, identifying patients with a dysregulated Hippo pathway is key to enhancing treatment impact. Although recent studies have derived RNAseq-based signatures, there remains a need for a reproducible and cost-effective method to measure the pathway activation. In recent years, deep learning applied to histology slides have emerged as an effective way to predict molecular information from a data modality available in clinical routine. Here, we trained models to predict YAP1/TEAD activity from H&E-stained histology slides in multiple cancers. The robustness of our approach was assessed in seven independent validation cohorts. Finally, we showed that histological markers of disease aggressiveness were associated with dysfunctional Hippo signaling.

bioinformatics↗

bioRxiv2021

Gene signature of circulating platelet-bound neutrophils is associated with poor prognosis in cancer patients

Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil-platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStream(R)X (ISX) imaging flow cytometer, we were not only allowed able to detect CD15+ CD14- CD36+ ITGA2B+ NPAs in both healthy donors (HDs) and cancer patients bloods, but we also showed that NPAs result from the binding of platelets preferentially to low-density neutrophils (LDNs) as opposed to normal-density neutrophils (NDNs). By re-analyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients derived NPAs possessed a distinct molecular signature compared with the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs-associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans-endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs-associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors. Novelty and ImpactPlatelets physically interact with peripheral blood neutrophils to form neutrophil-platelet aggregates (NPAs), known to promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. We showed that NPAs-associated neutrophils were a yet-unreported unique subset of circulating neutrophils associated with a worse patient prognosis in several cancer types. NPAs may hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors.

immunology↗