Meta-Analysis of Microdissected Breast Tumors Reveals Genes Regulated in the Stroma but Hidden in Bulk Analysis

Abstract

Background: transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, samples’ heterogeneity and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicate the interpretation of bulk transcriptomic profiles. Methods: we collected 48 microarray datasets of laser capture microdissected breast tumors, and performed a meta-analysis to identify robust lists of genes differentially expressed in these tumors. We created a database with carefully harmonized metadata to be used as a resource for the research community. Results: combining the results of multiple datasets improved the statistical power, and the analysis of stroma and epithelium separately allows identifying genes with different contribution in each compartment. Conclusions: our database can profitably help biomarkers’ discovery and is readily accessible through a user-friendly web interface (https://aurorasavino.shinyapps.io/metalcm/).

STAT3 induces breast cancer growth via ANGPTL4, MMP13 and STC1 secretion by cancer associated fibroblasts

“…TCGA data were from https://portal.gdc.cancer.gov/, METABRIC data from http://synapse.org/ (syn1757063), and additional breast cancer transcriptome datasets were obtained from package MetaGxBreast [51] (only datasets with at least 10000 probes). Stroma-related datasets were downloaded from Gene Expression Omnibus as pre-normalized expression matrices (Supplementary Table VI, part of the MetaLCM database [52]). All gene IDs were converted to HGNC symbols, and in case of more probes mapping to the same gene, the probe with the highest mean expression across dataset's samples was kept.…”

Contrast Subgraphs Allow Comparing Homogeneous and Heterogeneous Networks Derived from Omics Data

“…These cells can either restrain tumor growth or support cancer cells providing metabolites, growth factors and reshaping the extracellular matrix. Overall, nontumoral cells surrounding the tumor epithelium have been demonstrated to change their expression profiles [28] and to impact not only on tumor growth, but also on disease progression and metastasis, and on drug resistance [27, 38, 40]. In particular, the immune system plays a fundamental role in cancer progression: at tumor onset, cytotoxic immune cells recognize and kill tumor cells, driving the evolution of less immunogenic cancer cells able to evade immune detection [13].…”

“…In particular, the immune system plays a fundamental role in cancer progression: at tumor onset, cytotoxic immune cells recognize and kill tumor cells, driving the evolution of less immunogenic cancer cells able to evade immune detection [13]. Paradoxically, immune cells such as antiinflammatory M2 macrophages can have pro-tumoral effects [21] and their distribution and composition changes with tumorigenesis [11, 28]. For these reasons, immune cells are currently being investigated as potential therapeutic targets [8, 14].…”