Development of an arteriolar niche and self-renewal of breast cancer stem cells by lysophosphatidic acid/protein kinase D signaling

Yinan Jiang,Helen Krontiras,Herbert Chen,Douglas Hurst,Rachael Guenter,Roy Silverstein,Qi Cao,Reagan Hattaway,Qiming Jane Wang,Bin Ren,Adam W Beck,Jinjin Hao,Yehe Liu,Yichen Guo,Justin Lathia

doi:10.1038/s42003-021-02308-6

Abstract

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within the arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs likely via differential regulation of CD36 transcription. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 -CD36 signaling pathway may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and effectively eliminating CSCs.

Highlights

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence
ALDH1A1 served as a marker for BCSCs, whereas the co-staining of ephrin B2 and α-smooth muscle actin (α-SMA) served as markers of the arteriolar niche
Our current data suggest that BCSCs tend to be enriched within the arteriolar niche and that these cells may be plastic as they expressed high levels of ALDH1 marker[31,32], thereby contributing to tumor progression

Summary

Introduction

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. We hypothesized that the LPA/PKD-1 signaling axis regulates both arteriolar differentiation of the vascular endothelial cells and self-renewal of BCSCs. In this study, we highlight the existence of the arteriolar niche within the TME of BCs. Intriguingly, CD44+/ALDH1+ BCSCs tended to be enriched within the arteriolar niche, a location where bi-directional interactions occurred between arteriolar ECs and BCSCs. LPA/PKD-1 signaling induced arteriolar differentiation that may contribute to arteriolar niche development and directly promoted self-renewal of BCSCs. LPA/PKD-1 signaling induced arteriolar differentiation that may contribute to arteriolar niche development and directly promoted self-renewal of BCSCs These studies indicate that the LPA/PKD-1 signaling may play an essential role in tumor progression by nurturing the development of an arteriolar niche to enhance CSC self-renewal and directly promoting stemness features of cancer cells

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Conclusion