Biology subjects

Giglio, R. M.

Publications and source records attributed to Giglio, R. M..

2 recordsLinked to original sources

bioRxiv2024

Lineage-specific proteome remodeling of diverse lung cancer cells by targeted epigenetic inhibitors

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative molecular profiling of 10,621 proteins, these data reveal coordinated molecular remodeling of HDACi treated cancer cells. HDACi-regulated proteins differ greatly across cell lines with consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors. Together these data provide valuable insight into cell-type driven and heterogeneous responses that must be taken into consideration when monitoring molecular perturbations in culture models. We have also built a web interface for the extensive amount of data to allow users to explore the data as a resource for understanding chemical perturbation of diverse cell types.

cancer biology↗

bioRxiv2024

A heterogenous pharmaco-transcriptomic landscape induced by targeting a single oncogenic kinase

Over-activation of the epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR-targeted therapies have led to minimal clinical response. While delivery of EGFR inhibitors (EGFRis) to the brain constitutes a major challenge, how additional drug-specific features alter efficacy remains poorly understood. We introduce SCHEMATIC, which integrates multiplex single-cell chemical transcriptomics with deep-generative classification to resolve chemotype-specific and shared programs and apply it to to define the molecular response of glioblastoma to EGFRis. We identify programs that differ by the chemical properties of EGFRis, including induction of adaptive transcription and modulation of immunogenic gene expression. We find that induction of an adaptive transcriptional program is associated with persistence of surviving cells after EGFR inhibition, and that concurrent EGFR/PI3K inhibition attenuates this program. We also find that pro-immunogenic expression changes associated with a subset of tyrphostin-family EGFR inhibitors are accompanied by enhanced antigen-specific cytotoxic T-cell killing in vitro. Our study provides a framework that considers each agents unique and often unknown poly-pharmacology to prioritize compounds pre-clinically that induce favorable molecular responses.

genomics↗