Biology subjects

Pass, H.

Publications and source records attributed to Pass, H..

3 recordsLinked to original sources

bioRxiv2025

Cross-species analysis identifies genotype-driven vulnerabilities in lung adenocarcinoma

While three major genetic alteration subsets, characterized by mutations in STK11, KRAS, and EGFR, are seminal in driving tumorigenesis in LUAD, their distinct effects on tumor cells and the tumor microenvironment are not fully understood. Here, we map critical oncogenic subset-specific vulnerabilities by identifying conserved cell-type-specific reprogrammings between human and mouse LUAD. Through harmonized scRNA-seq analysis of 57 human and 18 mouse specimens, we unveil that genetic alterations impose genotype-specific immune imprints on the tumor microenvironment: KRAS is associated with a transitional immune state, whereas STK11 and EGFR mutations define discrete and contrasting immune phenotypes. We find that STK11-mutant tumors exhibit complement and interferon-rich immune microenvironments while EGFR-mutant tumors harbor a naive T cell-rich phenotype accompanied by a global HLA downregulation, stress-responsive alveolar macrophages marked by MARCO. In the epithelial compartments, cross-species analysis reveals metabolic dependencies, including OGDH in EGFR- and PDE4D in STK11-mutant cells. Statement of SignificanceThis study delineates oncogenotype-specific molecular and immune imprints in lung adenocarcinoma, revealing STK11-, KRAS-, and EGFR-mutated tumors as transcriptionally and immunologically discrete ecosystems. By mapping epithelial vulnerabilities alongside immune imprints, we unveil genotype-imposed dependencies that inform the rational development of precision therapies with direct translational relevance.

cancer biology↗

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↗

bioRxiv2023

Integrative Multi-omic Profiling of Two Human Decedents Receiving Pig Heart Xenografts Reveals Strong Perturbations in Early Immune-Cell and Cellular Metabolism Responses.

BackgroundRecent advances in xenotransplantation in living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use and first in human trials. Major obstacles remain though, including a lack of knowledge of the genetic incompatibilities between pig donors and human recipients which may led to harmful immune responses against the xenograft or dysregulation of normal physiology. In 2022 two pig heart xenografts were transplanted into two brain-dead human decedents with a minimized immunosuppression regime, primarily to evaluate onset of hyper-acute antibody mediated rejection and sustained xenograft function over 3 days. MethodsWe performed multi-omic profiling to assess the dynamic interactions between the pig and human genomes in the first two pig heart-xenografts transplants into human decedents. To assess global and specific biological changes that may correlate with immune-related outcomes and xenograft function, we generated transcriptomic, lipidomic, proteomic and metabolomics datasets, across blood and tissue samples collected every 6 hours over the 3-day procedures. ResultsSingle-cell datasets in the 3-day pig xenograft-decedent models show dynamic immune activation processes. We observe specific scRNA-seq, snRNA-seq and geospatial transcriptomic changes of early immune-activation leading to pronounced downstream T-cell activity and hallmarks of early antibody mediated rejection (AbMR) and/or ischemia reperfusion injury (IRI) in the first xenograft recipient. Using longitudinal multiomic integrative analyses from blood in addition to antigen presentation pathway enrichment, we also observe in the first xeno-heart recipient significant cellular metabolism and liver damage pathway changes that correlate with profound physiological dysfunction whereas, these signals are not present in the other xenograft recipient. ConclusionsSingle-cell and multiomics approaches reveal fundamental insights into early molecular immune responses indicative of IRI and/or early AbMR in the first human decedent, which was not evident in the conventional histological evaluations.

systems biology↗