Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis

Li, Peishan; Lu, Ming; Shi, Jiayuan; Gong, Zheng; Li, Hua; Li, Qing; Lim, Bora; Zhang, Xiang H.-F.; Chen, Xiaowen; Li, Sheng; Shultz, Leonard D.; Ren, Guosheng

doi:10.1038/s41590-020-0783-5

Cited by 155 publications

(131 citation statements)

References 51 publications

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“…PMN-MDSCs in the premetastatic niches may facilitate the escape of tumour cells by suppressing immune cells, inducing matrix remodelling and promoting angiogenesis 55 , which in turn facilitate the engraftment of tumour cells. Another mechanism of regulation of tumour metastasis was described in a recent study by Li et al 56 , who demonstrated, in a breast cancer model, that neutrophils accumulated neutral lipids via the repression of adipose triglyceride lipase activity. Neutrophil-specific deletion of adipose triglyceride lipase decreased metastasis in mice and lipid transfer from neutrophils to tumour cells was shown to facilitate metastasis 56 .…”

Section: Roles Of Mdscs In Cancermentioning

confidence: 90%

“…Another mechanism of regulation of tumour metastasis was described in a recent study by Li et al 56 , who demonstrated, in a breast cancer model, that neutrophils accumulated neutral lipids via the repression of adipose triglyceride lipase activity. Neutrophil-specific deletion of adipose triglyceride lipase decreased metastasis in mice and lipid transfer from neutrophils to tumour cells was shown to facilitate metastasis 56 . The authors reported that these cells suppressed NK cells, suggesting that they may be PMN-MDSCs.…”

Section: Roles Of Mdscs In Cancermentioning

confidence: 90%

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Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

2021

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Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.

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Section: Roles Of Mdscs In Cancermentioning

confidence: 90%

Section: Roles Of Mdscs In Cancermentioning

confidence: 90%

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

2021

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“…This work demonstrates that optical imaging of Bodipy FL c16 is important for lipid metabolism research. These studies are paramount to the successful translation of targeted metabolic therapies for TNBC and the plethora of other tumors that are dependent on fatty acids [ 57 , 63 , 82 ]. The drug screening protocol demonstrated here could also be applied to image the lung, liver, or brain through abdominal or cranial window chamber models, respectively [ 83 , 84 ].…”

Section: Discussionmentioning

confidence: 99%

“…The drug screening protocol demonstrated here could also be applied to image the lung, liver, or brain through abdominal or cranial window chamber models, respectively [ 83 , 84 ]. Tumors in each of these locations have reportedly shown a dysregulated lipid metabolism [ 82 , 85 , 86 ]. More invasive window chambers of non-superficial organs, such as liver or lung windows, would require terminal imaging sessions; therefore, only single time points could be captured without more advanced surgical techniques.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

Madonna

Duer

Lee

et al. 2021

Cancers

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Targeting a tumor’s metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical tumor models to guide development of new drugs that restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo and demonstrate its relevance to study both tumor metabolic reprogramming directly, as well as the effectiveness of drugs targeting lipid metabolism. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing, transgenic, triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 min, with the signal remaining stable during the 30–80 min post-injection period. We used the fluorescence at 60 min (Bodipy60), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene, consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays providing rich metabolic information at static time points and imaging approaches visualizing metabolism in whole organs at a reduced resolution.

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“…Neutrophils also serve as an energy source to fuel metastatic tumor cells. In a breast cancer model, infiltrating neutrophils are induced to store lipids upon interaction with resident mesenchymal cells in the lung so that when disseminated tumor cells (DTCs) arrive, neutrophils transfer their stored lipids to DTCs for their survival and proliferation (Li et al, 2020).…”

Section: Secondary Organ Colonizationmentioning

confidence: 99%

Organotypic Modeling of the Tumor Landscape

Haykal

Nahmias

Varon

et al. 2020

Front. Cell Dev. Biol.

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Cancer is a complex disease and it is now clear that not only epithelial tumor cells play a role in carcinogenesis. The tumor microenvironment is composed of non-stromal cells, including endothelial cells, adipocytes, immune and nerve cells, and a stromal compartment composed of extracellular matrix, cancer-associated fibroblasts and mesenchymal cells. Tumorigenesis is a dynamic process with constant interactions occurring between the tumor cells and their surroundings. Even though all connections have not yet been discovered, it is now known that crosstalk between actors of the microenvironment drives cancer progression. Taking into account this complexity, it is important to develop relevant models to study carcinogenesis. Conventional 2D culture models fail to represent the entire tumor microenvironment properly and the use of animal models should be decreased with respect to the 3Rs rule. To this aim, in vitro organotypic models have been significantly developed these past few years. These models have different levels of complexity and allow the study of tumor cells alone or in interaction with the microenvironment actors during the multiple stages of carcinogenesis. This review depicts recent insights into organotypic modeling of the tumor and its microenvironment all throughout cancer progression. It offers an overview of the crosstalk between epithelial cancer cells and their microenvironment during the different phases of carcinogenesis, from the early cell autonomous events to the late metastatic stages. The advantages of 3D over classical 2D or in vivo models are presented as well as the most promising organotypic models. A particular focus is made on organotypic models used for studying cancer progression, from the less complex spheroids to the more sophisticated body-on-a-chip. Last but not least, we address the potential benefits of these models in personalized medicine which is undoubtedly a domain paving the path to new hopes in terms of cancer care and cure.

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Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis

Cited by 155 publications

References 51 publications

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

Organotypic Modeling of the Tumor Landscape

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