Lost in translation: applying 2D intercellular communication via tunneling nanotubes in cell culture to physiologically relevant 3D microenvironments

Lou, Emil; O’Hare, P.A.G.; Subramanian, Subbaya; Steer, Clifford J.

doi:10.1111/febs.13946

Cited by 20 publications

(15 citation statements)

References 66 publications

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“…We next asked how macrophage cytoplasm is delivered to tumor cells. There are at least two mechanisms of cytoplasmic transfer – transfer of molecules extracellularly via secretion of extracellular vesicles (EVs), and transfer of molecules through cell-to-cell contact (Lou et al, 2017; McCoy-Simandle et al, 2016; Weidle et al, 2017)). The migration-promoting cytoplasmic transfer between tumor cells described by Zomer et al was via systemic transfer of EVs, however given the close and sustained physical interactions between macrophages and tumor cells observed in our zebrafish studies, we hypothesized that the cytoplasmic transfer from macrophages to tumor cells is cell-contact mediated.…”

Section: Resultsmentioning

confidence: 99%

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo

et al. 2017

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Summary Interactions between tumor cells and tumor-associated macrophages play critical roles in the initiation of tumor cell motility. To capture the cellular interactions of the tumor microenvironment with high-resolution imaging, we directly visualized tumor cells and their interactions with macrophages in zebrafish. Live-imaging in zebrafish revealed that macrophages are dynamic, yet maintain sustained contact with tumor cells. Additionally, the recruitment of macrophages to tumor cells promotes tumor cell dissemination. Using a Cre/LoxP strategy, we found that macrophages transfer cytoplasm to tumor cells in zebrafish and mouse models. Remarkably, macrophage cytoplasmic transfer correlated with melanoma cell dissemination. We further found that macrophages transfer cytoplasm to tumor cells upon cell contact in vitro. Thus, we present a model in which macrophage/tumor cell contact allows for the transfer of cytoplasmic molecules from macrophages to tumor cells corresponding to increased tumor cell motility and dissemination.

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Section: Resultsmentioning

confidence: 99%

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo

et al. 2017

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“…TNTs have been previously reported to mediate specific direct cellcell contact between macrophages (Hanna et al, 2017;Hase et al, 2009) as well as between tumor cells (Ady et al, 2014;Lou et al, 2012Lou et al, , 2017bOsswald et al, 2015). Given the important role of macrophages in breast cancer progression and the existence of TNTs in both contexts, we investigated whether heterotypic TNTs form between macrophages and tumor cells.…”

Section: Formation Of Heterotypic Tnts Between Tumor Cells and Macropmentioning

confidence: 99%

Tunneling nanotubes, a novel mode of tumor cell–macrophage communication in tumor cell invasion

Hanna

McCoy-Simandle

Leung

et al. 2019

Journal of Cell Science

103

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The interaction between tumor cells and macrophages is crucial in promoting tumor invasion and metastasis. In this study, we examined a novel mechanism of intercellular communication, namely membranous actin-based tunneling nanotubes (TNTs), that occurs between macrophages and tumor cells in the promotion of macrophage-dependent tumor cell invasion. The presence of heterotypic TNTs between macrophages and tumor cells induced invasive tumor cell morphology, which was dependent on EGF-EGFR signaling. Furthermore, reduction of a protein involved in TNT formation, M-Sec (TNFAIP2), in macrophages inhibited tumor cell elongation, blocked the ability of tumor cells to invade in 3D and reduced macrophage-dependent long-distance tumor cell streaming in vitro. Using an in vivo zebrafish model that recreates macrophagemediated tumor cell invasion, we observed TNT-mediated macrophage-dependent tumor cell invasion, distant metastatic foci and areas of metastatic spread. Overall, our studies support a role for TNTs as a novel means of interaction between tumor cells and macrophages that leads to tumor progression and metastasis.

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“…The monolayer cells under 2D culture condition completely differ from in vivo status where cells grow in three dimensions (3D), in terms of cell morphology, cell-to-cell interactions, growth behavior, and interactions with extracellular matrix 30 . It has been well demonstrated that 2D cell monolayer is unable to represent the physiology of in vivo 3D tissues or organs, due to the substantially different microenvironment (e.g., mechanical and biochemical properties) in tissue architecture [36][37][38][39][40][41] .…”

mentioning

confidence: 99%

3D cell culture stimulates the secretion of in vivo like extracellular vesicles

Thippabhotla

Zhong

2019

Sci Rep

183

137

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For studying cellular communications ex-vivo, a two-dimensional (2D) cell culture model is currently used as the “gold standard”. 2D culture models are also widely used in the study of RNA expression profiles from tumor cells secreted extracellular vesicles (EVs) for tumor biomarker discovery. Although the 2D culture system is simple and easily accessible, the culture environment is unable to represent in vivo extracellular matrix (ECM) microenvironment. Our study observed that 2D- culture derived EVs showed significantly different profiles in terms of secretion dynamics and essential signaling molecular contents (RNAs and DNAs), when compared to the three-dimensional (3D) culture derived EVs. By performing small RNA next-generation sequencing (NGS) analysis of cervical cancer cells and their EVs compared with cervical cancer patient plasma EV-derived small RNAs, we observed that 3D- culture derived EV small RNAs differ from their parent cell small RNA profile which may indicate a specific sorting process. Most importantly, the 3D- culture derived EV small RNA profile exhibited a much higher similarity (~96%) to in vivo circulating EVs derived from cervical cancer patient plasma. However, 2D- culture derived EV small RNA profile correlated better with only their parent cells cultured in 2D. On the other hand, DNA sequencing analysis suggests that culture and growth conditions do not affect the genomic information carried by EV secretion. This work also suggests that tackling EV molecular alterations secreted into interstitial fluids can provide an alternative, non-invasive approach for investigating 3D tissue behaviors at the molecular precision. This work could serve as a foundation for building precise models employed in mimicking in vivo tissue system with EVs as the molecular indicators or transporters. Such models could be used for investigating tumor biomarkers, drug screening, and understanding tumor progression and metastasis.

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Lost in translation: applying 2D intercellular communication via tunneling nanotubes in cell culture to physiologically relevant 3D microenvironments

Cited by 20 publications

References 66 publications

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo

Tunneling nanotubes, a novel mode of tumor cell–macrophage communication in tumor cell invasion

3D cell culture stimulates the secretion of in vivo like extracellular vesicles

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