Hjelmeland, A. B. | Search bioRxiv

bioRxiv2023

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates

Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e, limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/532074v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1c5d402org.highwire.dtl.DTLVardef@e1dc86org.highwire.dtl.DTLVardef@54e6feorg.highwire.dtl.DTLVardef@96856_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2021

Horizontal mitochondrial transfer from the microenvironment increases glioblastoma tumorigenicity

While dynamic microenvironmental interactions drive tumor growth and therapeutic resistance, the underlying direct cell-cell communication mechanisms remain poorly understood. We identified horizontal mitochondrial transfer as a mechanism that enhances tumorigenesis in glioblastoma. This transfer occurs primarily from brain-resident cells, including astrocytes, and can be appreciated in vitro and in vivo through intercellular connections between GBM cells and non-malignant host cells. The acquisition of astrocyte mitochondria drives an overall enhancement of mitochondrial membrane potential and metabolic capacity, while increasing glioblastoma cell self-renewal and tumor-initiating capacity. Collectively, our findings demonstrate that mitochondrial transfer augments the tumorigenic capacity of glioblastoma cells and reveals a previously unknown cell-cell communication mechanism that drives tumor growth. One-Sentence SummaryMitochondrial transfer from astrocytes to glioblastoma alters metabolic profile and enhances the tumor-initiation capacity.

cancer biology↗