Integrating bulk and single-cell RNA sequencing data reveals the relationship between intratumor microbiome signature and host metabolic heterogeneity in breast cancer

Abstract

IntroductionNowadays, it has been recognized that gut microbiome can indirectly modulate cancer susceptibility or progression. However, whether intratumor microbes are parasitic, symbiotic, or merely bystanders in breast cancer is not fully understood. Microbial metabolite plays a pivotal role in the interaction of host and microbe via regulating mitochondrial and other metabolic pathways. And the relationship between tumor-resident microbiota and cancer metabolism remains an open question.Methods1085 breast cancer patients with normalized intratumor microbial abundance data and 32 single-cell RNA sequencing samples were retrieved from public datasets. We used the gene set variation analysis to evaluate the various metabolic activities of breast cancer samples. Furthermore, we applied Scissor method to identify microbe-associated cell subpopulations from single-cell data. Then, we conducted comprehensive bioinformatic analyses to explore the association between host and microbe in breast cancer.ResultsHere, we found that the metabolic status of breast cancer cells was highly plastic, and some microbial genera were significantly correlated with cancer metabolic activity. We identified two distinct clusters based on microbial abundance and tumor metabolism data. And dysregulation of the metabolic pathway was observed among different cell types. Metabolism-related microbial scores were calculated to predict overall survival in patients with breast cancer. Furthermore, the microbial abundance of the specific genus was associated with gene mutation due to possible microbe-mediated mutagenesis. The infiltrating immune cell compositions, including regulatory T cells and activated NK cells, were significantly associated with the metabolism-related intratumor microbes, as indicated in the Mantel test analysis. Moreover, the mammary metabolism-related microbes were related to T cell exclusion and response to immunotherapy.ConclusionsOverall, the exploratory study shed light on the potential role of the metabolism-related microbiome in breast cancer patients. And the novel treatment will be realized by further investigating the metabolic disturbance in host and intratumor microbial cells.

Comprehensive analysis of microbial content in whole-genome sequencing samples from The Cancer Genome Atlas project

“…As we explained previously 4 , these overcounts can be attributed in part to the inclusion of numerous draft genomes (which themselves contain contaminants) in the database used for the metagenomic analysis. The work of Poore et al 1 has been used in at least a dozen other studies [16][17][18][19][20][21][22][23][24][25][26][27] that downloaded their read count data and then published findings based on that data, and another recent study 28 similarly based its results on the "mycobiome" data from Narunsky-Haziza et al 2 Our analyses here used a much cleaner database, containing only complete bacterial genomes, which in turn yielded much lower and more accurate counts for the microbial species we identified. We hope that by providing a more accurate set of read counts for the same TCGA samples, our new dataset can serve as a valuable public resource, enabling researchers to better distinguish genuine microbial signals from background noise and contaminants in future investigations.…”

Intratumor microbiome: selective colonization in the tumor microenvironment and a vital regulator of tumor biology

“…In intrahepatic cholangiocarcinoma, the intratumor microbiota Paraburkholderia fungorum was significantly enriched in paracancerous tissues, which could inhibit tumor growth through alanine, aspartate, and glutamate metabolism 91 . And in breast cancer, integrating bulk and single‐cell RNA sequencing data revealed that the intratumor microbiome was significantly associated with metabolic heterogeneity in breast cancers, highlighting the need for further mechanistic investigations 92 . These results indicate that the intratumor microbiome may influence many aspects of cancer cells, but may differ between different cancer types; more specific and comparative investigations are thus needed.…”

“… 91 And in breast cancer, integrating bulk and single‐cell RNA sequencing data revealed that the intratumor microbiome was significantly associated with metabolic heterogeneity in breast cancers, highlighting the need for further mechanistic investigations. 92 These results indicate that the intratumor microbiome may influence many aspects of cancer cells, but may differ between different cancer types; more specific and comparative investigations are thus needed.…”

From Reductionistic Approach to Systems Immunology Approach for the Understanding of Tumor Microenvironment

“…Advances in other "omic" techniques, such as proteomics via mass spectrometry and integrated technological methods, have also been able to comprehend communication networks and mechanisms of processes like host defense and tissue homeostasis [37]. Additionally, "omic" methods focused on understanding the tissue microbiome can provide insights as well, given the role of microbial species in both homeostatic or inflammatory events during dysbiosis [38,39], exemplifying yet another method that can be used to understand the TME at the systems level. Systems-level approaches certainly seem daunting, given the immense amount of information and knowledge required to fully understand the TME, but many of these novel "omic" techniques, like microbiome composition, represent avenues to further study the microenvironment.…”