Shang et al. Cell Death and Disease (2020) 11:990 https://doi.org/10.1038/s41419-020-03207-0 Cell Death & Disease REVIEW ARTICLE Open Access The dynamic behavior of lipid droplets in the pre-metastatic niche Chunliang Shang1,JieQiao 2,3,4,5,6 and Hongyan Guo1 Abstract The pre-metastatic niche is a favorable microenvironment for the colonization of metastatic tumor cells in specific distant organs. Lipid droplets (LDs, also known as lipid bodies or adiposomes) have increasingly been recognized as lipid-rich, functionally dynamic organelles within tumor cells, immune cells, and other stromal cells that are linked to diverse biological functions and human diseases. Moreover, in recent years, several studies have described the indispensable role of LDs in the development of pre-metastatic niches. This review discusses current evidence related to the biogenesis, composition, and functions of LDs related to the following characteristics of the pre-metastatic niche: immunosuppression, inflammation, angiogenesis/vascular permeability, lymphangiogenesis, organotropism, reprogramming. We also address the function of LDs in mediating pre-metastatic niche formation. The potential of LDs as markers and targets for novel antimetastatic therapies will be discussed. neutrophils, macrophages, and dendritic cells in Facts diverse cancer types. ● ● We discuss the potential roles of LDs in mediating 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Lipid droplets have increasingly been recognized as pre-metastatic niche formation. lipid-rich, functionally dynamic organelles within ● Treatment of the LD-associated key enzymes tumor cells, immune cells, and other stromal cells significantly abolished tumor cell adhesion to that are linked to diverse biological functions and endothelial cells and reduced the recruitment of human diseases. immune cells in pre-metastatic niche. ● This review discuss the current evidence related to the functions of LDs related to the following characteristics of the pre-metastatic niche: Open questions immunosuppression, inflammation, angiogenesis/ vascular permeability, lymphangiogenesis, ● What is the definition of ‘LDs’ and its biogenesis in organotropism, reprogramming. tumor microenvironment cells? ● The molecular marker of LDs, PLIN2, was ● What is the maturation process of LDs in tumor pre- significantly associated with tumor purity and metastatic niche? infiltration of B cells, CD4+ T cells, CD8+ T cells, ● How does LDs regulate pre-metastatic niche formation? ● LDs reprograming represents promising cancer therapy, what are the limitations and adverse Correspondence: Jie Qiao ([email protected]) or Hongyan Guo reactions? How to improve treatment efficiency? ([email protected]) ● 1Department of Obstetrics and Gynecology, Peking University Third Hospital, What should be further studied about LDs in pre- 100191 Beijing, China metastatic niche? 2Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, 100191 Beijing, China Full list of author information is available at the end of the article Edited by A. Finazzi-Agrò © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Shang et al. Cell Death and Disease (2020) 11:990 Page 2 of 13 Introduction is not only determined by the mechanical dynamics of Metastasis is the primary cause of cancer morbidity and hematogenous flow3; Steven Paget’s “seed and soil” theory mortality1. Tumor metastasis is a complicated process is also a pivotal milestone in explaining metastatic colo- termed the invasion-metastasis cascade, which involves nization4,5. However, why are only a few tumor cells multiple sequential and interrelated steps and several capable of becoming DTCs and leaving the primary biochemical events. The metastatic cascade comprises the tumor? Are DTCs more prone to lymphatic or blood following sequential steps2: (1) tumor cells gain invasive metastasis? Why does the development of metastases activity and detach from the primary tumor site; (2) dis- occur selectively in certain organs but not others6,7? seminated tumor cells (DTCs) break through the base- Moreover, what is the interplay between intrinsic tumor ment membrane (BM) and extracellular matrix (ECM) cell properties and the interactions between tumor cells and invade the blood and/or lymphatic vessels; (3) cir- and multiple microenvironments? culating tumor cells (CTCs) escape immune elimination A wealth of research has revealed that distant metastatic and survival in lymphatic and/or vascular circulation; (4) organs are not passive recipients of CTCs but instead CTCs initiate extravasation, crossing from the vascular selectively and actively prepare the secondary micro- lumen into the organ parenchyma; and (5) CTCs survive environment in response to the primary tumor for CTC and subsequently proliferate to form overt metastases in a colonization before the arrival of CTCs8,9. These pre- secondary organ/site. Therefore, metastatic dissemination conditioned microenvironments are termed pre- a DAPI α-actin BODIPY493/503 Merge 200X 400X b membrane trafficking PLIN protein inflammatory mediator production Phospholipid monolayer Immune responses Cholesteryl esters tumor microenvironment regulation Triacylglycerol energy metabolism cell signaling Fig. 1 Structure and basic function of lipid bodies. a Fluorescence microscopy image shows LDs with double staining with BODIPY 493/503 dye (green) and Hoechst in the macrophage cells. b Schematic representation of the structural composition of LD and the basic function of LD is listed in the right. Official journal of the Cell Death Differentiation Association Shang et al. Cell Death and Disease (2020) 11:990 Page 3 of 13 metastatic niches (PMNs) and were first described by organelles that exist in almost all eukaryotic cells (Fig. 1a). Kaplan, R. N. et al.10. The significance of the PMN has Unlike most other intracellular organelles, LDs are sur- received increasing attention in recent years11,12. Cao8 rounded by a monolayer of phospholipids composed of a summarized six characteristics that define the PMN: hydrophobic core of triacylglycerol (TAG) and cholesteryl inflammation, immunosuppression, angiogenesis/vascular esters (CEs) and coated with hundreds of proteins, permeability, lymphangiogenesis, organotropism, and including the perilipin (PLIN) family18 (Fig. 1b). Among reprogramming. Furthermore, primary tumor-derived the PLIN family, PLIN2 as a LD marker, is universally molecular components (soluble factors and extracellular expressed in nearly all tissues19. In the early 1960s, LDs vesicles13), tumor-recruited bone marrow-derived cells were reported to be abundant in tumor cells and might (BMDCs)14, regulatory/suppressive immune cells15 and assist in the diagnosis of Burkitt’s tumor20,21. With key the future metastatic organ-specific microenvironment research findings showing that prostaglandin E2 (PGE2) have been identified as the crucial determinants for PMN synthesis in LDs can promote colon cancer cell pro- formation. Based on the above characteristics and PMN liferation22, considerable attention has been paid to the components, the formation of PMNs covers almost all of role of LDs in cancer involving membrane trafficking, the key events of tumor metastasis. It is extremely energy metabolism, cell signaling, immune responses, important to explore the spatiotemporal regulatory rela- inflammatory mediator production, and tumor micro- – tionship between these PMN characteristics of and who environment regulation23 25. Interestingly, growing evi- the probable prime culprit is at different stages of PMN dence indicates that, compared with the Warburg effect in formation. cancer cells, reprogramming lipid metabolism may pro- Lipid droplets are cytoplasmic lipid-rich organelles that vide a selective advantage for the tumor metastatic pro- are recognized as platforms with multiple functions in cess26. Our study27 also confirmed that the accumulation cancers16,17. LDs were initially perceived as static energy of LDs enhances lymphangiogenesis and the storage deposits, such as glycogen particles but are epithelial–mesenchymal transition (EMT) of tumor cells, increasingly described as dynamic and inducible spherical resulting in lymph node (LN) metastasis of cervical Budding and De novo formation Hydrophobic lipid mass formation in via acquisition of LDs proteins the ER membrane Cholesteryl LDs esters neutral lipid synthesis within ER Triacy lglycerol Budding DGAT2 LD E a DGAT1 Seipin Seipin ER Lumen Choles tery l “Egg” LDs es ters b Cytoplasma Triac ylglycerol ER Lumen “Cup” Ribosomes LDs c ER ER Fig. 2 Models of lipid droplet formation. a The “budding model”: