Single-Cell RNA-seq Reveals Obesity-Induced Alterations in the Brca1-Mutated Mammary Gland Microenvironment.

Pang-Kuo Lo,Qun Zhou,Yuan Yao

doi:10.3390/cancers12082235

Pang-Kuo Lo, Qun Zhou + Show 1 more

Open Access

https://doi.org/10.3390/cancers12082235

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Abstract

Clinical and experimental studies have shown that obesity increases the development and progression of breast cancer. The impact of obesity on the tumor microenvironment plays an important role in tumorigenesis, yet the precise mechanisms underlying obesity-mediated effects on cell-to-cell communication within the tumor microenvironment have been difficult to define. In this study, we conducted single-cell RNA sequencing (scRNA-seq) studies to investigate the impact of high-fat diet (HFD)-induced obesity on transcriptomic landscapes of stromal and immune cells in mammary glands of Brca1−/−; p53+/− mice, an animal breast cancer model. Hierarchical clustering and gene pathway enrichment analyses of scRNA-seq data showed that five different subtypes of stromal fibroblasts existed in mouse Brca1-mutated mammary glands. HFD-induced obesity led to upregulated expression of extracellular matrix (ECM) genes (Col3a1, Col6a3, Eln, and Sparc) and downregulated expression of immunoregulatory genes (Iigp1 and Cxcl10) in these stromal subtype cells. These findings, taken together, suggest that obesity alters the ECM composition and immune ecosystem through modulating the functionality of mammary stromal fibroblasts. Moreover, scRNA-seq analysis of mammary immune cells indicated that HFD-induced obesity promoted the generation and/or recruiting of pro-tumorigenic M2 macrophages in mammary glands. Our studies provide new insight into a mechanistic paradigm wherein obesity modulates the functions of stromal and immune cells to create the tumorigenic microenvironment for promoting breast tumorigenesis.

Highlights

Obesity has been recognized as a leading public health problem throughout the world [1].Roughly two-thirds United States (US) people are overweight (Body Mass Index (BMI) ≥ 25 kg/m2) and over 50%of these overweight people are obese (BMI ≥ 30 kg/m2) [2]
We only focused on the impact of high-fat diet (HFD)-induced obesity on stromal fibroblasts and immune cells
Given that four out of six upregulated genes are related to the extracellular matrix (ECM), our findings suggest that HFD-induced obesity alters the functionality of mammary stromal fibroblasts to change the composition of the ECM in mammary glands of Brca1−/−; p53+/− mice

Summary

Introduction

Two-thirds US people are overweight (Body Mass Index (BMI) ≥ 25 kg/m2) and over 50%. Of these overweight people are obese (BMI ≥ 30 kg/m2) [2]. An increasing number of large-cohort studies have demonstrated that obesity is susceptible to a risk of diseases, in particular cancer [1,2,3]. Multiple mechanisms have been revealed to account for the correlation between obesity and breast cancer, such as obesity-induced alterations in adipose endocrine functions, systemic immunity and metabolic homeostasis [9,10,11,12,13]. The exact mechanisms underlying obesity-mediated breast cancer progression remain incomplete

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