Biology subjects

Stahlberg, A.

Publications and source records attributed to Stahlberg, A..

3 recordsLinked to original sources

bioRxiv2024

Aging promotes lung cancer metastasis through epigenetic ATF4 induction

Lung cancer is primarily a disease of the elderly. Despite shared molecular changes between aging and cancer 1 - such as permissive chromatin states and deregulated protein homeostasis - studies on physiologically aged models of human lung cancer are lacking. Here, we show that aging alters the progression of KRAS-driven non-small cell lung cancer (NSCLC), promoting metastasis while suppressing primary lung tumor growth. Clinically, a multicenter analysis of all consecutively diagnosed NSCLC cases in Western Sweden over a 3-year period confirmed increased metastasis and smaller primary tumor size with age in KRAS-driven NSCLC. In addition, primary lung tumor cultures derived from older mice demonstrated an increased metastatic phenotype. Unbiased transcriptomic and epigenomic analyses identified ATF4, a major arm of the unfolded protein response (UPR), as a driver of aging-induced lung cancer metastasis. Furthermore, we found that the age-associated increase in ATF4 fuels metastatic dissemination through metabolic rewiring, including increased glutaminolysis. Finally, we report that pharmacological inhibition of glutaminase effectively suppressed aging-induced metastasis. Our findings suggest a novel adjuvant therapy for human lung cancer by targeting aging-induced metabolic plasticity, highlighting the need to consider the biology of aging in the development of cancer therapy.

cancer biology↗

bioRxiv2019

DIscBIO: a user-friendly pipeline for biomarker discovery in single-cell transcriptomics

The growing attention toward the benefits of single-cell RNA sequencing (scRNA-seq) is leading to a myriad of computational packages for the analysis of different aspects of scRNA-seq data. For researchers without advanced programing skills, it is very challenging to combine several packages in order to perform the desired analysis in a simple and reproducible way. Here we present DIscBIO, an open-source, multi-algorithmic pipeline for easy, efficient and reproducible analysis of cellular sub-populations at the trasncriptomic level. The pipeline integrates multiple scRNA-seq packages and allows biomarker discovery with decision trees and gene enrichment analysis in network context using single-cell sequencing read counts through clustering and differential analysis. DIscBIO is freely available as an R package. It can be run either in command-line mode or through a computational pipeline using Jupyter notebooks. We also provide a user-friendly, cloud version of the notebook for researchers with very limited programming skills. We showcase all pipeline features using two scRNA-seq datasets. The first dataset consists of circulating tumor cells from patients with breast cancer. The second one is a cell cycle regulation datatset in myxoid liposarcoma. All analyses are available as notebooks that integrate in a sequential narrative R code with explanatory text and output data and images. These notebooks can be used as tutorials for training purposes and will guide researchers to explore their scRNA-seq data.

bioinformatics↗

bioRxiv2018

Elevated pyrimidine dimer formation at distinct genomic bases underlie promoter mutation hotspots in UV-exposed cancers

Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations have also been suggested to be due to locally inhibited DNA repair or, alternatively, locally increased propensity for UV damage. Here, we provide evidence that base-specific elevations in the efficacy of UV lesion formation underlie these mutations. First, we find that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER), ruling out inhibited repair. Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit a strong base-specific increase in CPD formation frequency. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory regions, we conclude that the most recurrently mutated individual DNA bases arise instead due to locally favorable conditions for UV damage formation, thus explaining a key phenomenon in whole-genome cancer analyses.

cancer biology↗