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The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology...
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The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (25 April 2024) | Viewed by 25478

Special Issue Editor

Dr. Emil Lou

E-Mail Website1 Website2
Guest Editor
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
Interests: intercellular communication; tumor-stromal interactions; tunneling nanotubes; tumor microtubes; cellular protrusions; cancer biomarkers; chemoresistance; cancer cell biology; cellular oncology; molecular oncology; precision medicine

Special Issue Information

Dear Colleagues,

The dynamic and continuously evolving tumor microenvironment plays a crucial role in cancer progression and therapeutic resistance, but many of the underlying cellular mechanisms are still being elucidated. Even with better understanding of molecular oncology and identification of genomic drivers of these processes, there has been a relative lag in identifying and appreciating the important roles of cellular oncology in both invasion and resistance.

Intercellular communication is a vital process that unifies and synchronizes the diverse components of the tumor microenvironment. Increased spotlight on the many effects of extracellular vesicles (EV) over the past decade has cast a brighter light on the importance of intercellular communication. And yet even with this advance, other niches of intratumoral communication merit equal attention in investigation. Tunneling nanotubes (TNTs), tumor microtubes (TMs), cytonemes, and other similar forms of intercellular protrusions fill that niche and have rapidly gained more attention in the past few years.

These protrusions constitute a unique and emerging field of cell biology characterized by long ultrafine cellular conduits that extend and form direct connections between distant cells, mediating transfer of cell cargo such as mitochondria, exosomes, genetic material such as microRNAs and messenger RNAs, and even oncogenic drivers such as RAS. However, many of their functional roles in mediating tumor growth and evolution of the tumor microenvironment remain unknown. These conduits are literally physical bridges that stimulate formation of syncytial networks of dispersed cells amidst the intercellular matrix and surrounding stroma. Emerging evidence suggests that these TNTs and TMs provide an identifiable cellular mechanism for induction and emergence of drug resistance as well as contributing to increases in invasive and metastatic potential. They have been imaged in vitro and also in vivo and ex vivo in tumors from human patients as well as animal models, thus not only proving their existence in the TME, but opening further speculation about their exact role in the dynamic niche of tumor ecosystems.

This Special Issue of Cancers, focusing on this important and exciting field of cancer cell biology, will shine even greater spotlight on research focused on the role of these cellular protrusions in a spectrum of cancers. We welcome submission of manuscripts from researchers of all backgrounds studying these structures, and hope that this issue will serve the community as a virtual ‘meeting point’ for all. Each report on TNTs, TMs, and similar protrusions moves the field closer to identifying specific biomarkers and the various functions of these protrusions in cancer, and also in other human diseases. If these structures are truly vital to the synergistic cooperation of cells within the tumor microenvironment, then disrupting this novel route of cell-cell communication will develop as a new strategy for treatment of invasive cancers.


Dr. Emil Lou
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • tunneling nanotubes
  • tumor microtubes
  • intercellular communication
  • pathophysiology of cancer
  • cancer cell biology
  • tumor biology
  • tumor imaging
  • intravital microscopy

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Published Papers (6 papers)

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Research

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17 pages, 2178 KiB  
Article
Macrophages Promote Tumor Cell Extravasation across an Endothelial Barrier through Thin Membranous Connections
by Alessandro Genna, Camille L. Duran, David Entenberg, John S. Condeelis and Dianne Cox
Cancers 2023, 15(7), 2092; https://doi.org/10.3390/cancers15072092 - 31 Mar 2023
Cited by 4 | Viewed by 2441
Abstract
Macrophages are important players involved in the progression of breast cancer, including in seeding the metastatic niche. However, the mechanism by which macrophages in the lung parenchyma interact with tumor cells in the vasculature to promote tumor cell extravasation at metastatic sites is [...] Read more.
Macrophages are important players involved in the progression of breast cancer, including in seeding the metastatic niche. However, the mechanism by which macrophages in the lung parenchyma interact with tumor cells in the vasculature to promote tumor cell extravasation at metastatic sites is not clear. To mimic macrophage-driven tumor cell extravasation, we used an in vitro assay (eTEM) in which an endothelial monolayer and a matrigel-coated filter separated tumor cells and macrophages from each other. The presence of macrophages promoted tumor cell extravasation, while macrophage conditioned media was insufficient to stimulate tumor cell extravasation in vitro. This finding is consistent with a requirement for direct contact between macrophages and tumor cells. We observed the presence of Thin Membranous Connections (TMCs) resembling similar structures formed between macrophages and tumor cells called tunneling nanotubes, which we previously demonstrated to be important in tumor cell invasion in vitro and in vivo. To determine if TMCs are important for tumor cell extravasation, we used macrophages with reduced levels of endogenous M-Sec (TNFAIP2), which causes a defect in tunneling nanotube formation. As predicted, these macrophages showed reduced macrophage-tumor cell TMCs. In both, human and murine breast cancer cell lines, there was also a concomitant reduction in tumor cell extravasation in vitro when co-cultured with M-Sec deficient macrophages compared to control macrophages. We also detected TMCs formed between macrophages and tumor cells through the endothelial layer in the eTEM assay. Furthermore, tumor cells were more frequently found in pores under the endothelium that contain macrophage protrusions. To determine the role of macrophage-tumor cell TMCs in vivo, we generated an M-Sec deficient mouse. Using an in vivo model of experimental metastasis, we detected a significant reduction in the number of metastatic lesions in M-Sec deficient mice compared to wild type mice. There was no difference in the size of the metastases, consistent with a defect specific to tumor cell extravasation and not metastatic outgrowth. Additionally, with an examination of time-lapse intravital-imaging (IVI) data sets of breast cancer cell extravasation in the lungs, we could detect the presence of TMCs between extravascular macrophages and vascular tumor cells. Overall, our data indicate that macrophage TMCs play an important role in promoting the extravasation of circulating tumor cells in the lungs. Full article
(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)
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18 pages, 4448 KiB  
Article
TNTdetect.AI: A Deep Learning Model for Automated Detection and Counting of Tunneling Nanotubes in Microscopy Images
by Yasin Ceran, Hamza Ergüder, Katherine Ladner, Sophie Korenfeld, Karina Deniz, Sanyukta Padmanabhan, Phillip Wong, Murat Baday, Thomas Pengo, Emil Lou and Chirag B. Patel
Cancers 2022, 14(19), 4958; https://doi.org/10.3390/cancers14194958 - 10 Oct 2022
Cited by 4 | Viewed by 3584
Abstract
Background: Tunneling nanotubes (TNTs) are cellular structures connecting cell membranes and mediating intercellular communication. TNTs are manually identified and counted by a trained investigator; however, this process is time-intensive. We therefore sought to develop an automated approach for quantitative analysis of TNTs. Methods: [...] Read more.
Background: Tunneling nanotubes (TNTs) are cellular structures connecting cell membranes and mediating intercellular communication. TNTs are manually identified and counted by a trained investigator; however, this process is time-intensive. We therefore sought to develop an automated approach for quantitative analysis of TNTs. Methods: We used a convolutional neural network (U-Net) deep learning model to segment phase contrast microscopy images of both cancer and non-cancer cells. Our method was composed of preprocessing and model development. We developed a new preprocessing method to label TNTs on a pixel-wise basis. Two sequential models were employed to detect TNTs. First, we identified the regions of images with TNTs by implementing a classification algorithm. Second, we fed parts of the image classified as TNT-containing into a modified U-Net model to estimate TNTs on a pixel-wise basis. Results: The algorithm detected 49.9% of human expert-identified TNTs, counted TNTs, and calculated the number of TNTs per cell, or TNT-to-cell ratio (TCR); it detected TNTs that were not originally detected by the experts. The model had 0.41 precision, 0.26 recall, and 0.32 f-1 score on a test dataset. The predicted and true TCRs were not significantly different across the training and test datasets (p = 0.78). Conclusions: Our automated approach labeled and detected TNTs and cells imaged in culture, resulting in comparable TCRs to those determined by human experts. Future studies will aim to improve on the accuracy, precision, and recall of the algorithm. Full article
(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)
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16 pages, 12697 KiB  
Article
MAPK Signaling Is Required for Generation of Tunneling Nanotube-Like Structures in Ovarian Cancer Cells
by Jennifer M. Cole, Richard Dahl and Karen D. Cowden Dahl
Cancers 2021, 13(2), 274; https://doi.org/10.3390/cancers13020274 - 13 Jan 2021
Cited by 9 | Viewed by 3180
Abstract
Ovarian cancer (OC) cells survive in the peritoneal cavity in a complex microenvironment composed of diverse cell types. The interaction between tumor cells and non-malignant cells is crucial to the success of the metastatic process. Macrophages activate pro-metastatic signaling pathways in ovarian cancer [...] Read more.
Ovarian cancer (OC) cells survive in the peritoneal cavity in a complex microenvironment composed of diverse cell types. The interaction between tumor cells and non-malignant cells is crucial to the success of the metastatic process. Macrophages activate pro-metastatic signaling pathways in ovarian cancer cells (OCCs), induce tumor angiogenesis, and orchestrate a tumor suppressive immune response by releasing anti-inflammatory cytokines. Understanding the interaction between immune cells and tumor cells will enhance our ability to combat tumor growth and dissemination. When co-cultured with OCCs, macrophages induce projections consistent with tunneling nanotubes (TnTs) to form between OCCs. TnTs mediate transfer of material between cells, thus promoting invasiveness, angiogenesis, proliferation, and/or therapy resistance. Macrophage induction of OCC TnTs occurs through a soluble mediator as macrophage-conditioned media potently induced TnT formation in OCCs. Additionally, EGFR-induced TnT formation in OCCs through MAPK signaling may occur. In particular, inhibition of ERK and RSK prevented EGFR-induced TnTs. TnT formation in response to macrophage-conditioned media or EGFR signaling required MAPK signaling. Collectively, these studies suggest that inhibition of ERK/RSK activity may dampen macrophage-OCC communication and be a promising therapeutic strategy. Full article
(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)
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25 pages, 4257 KiB  
Article
Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells
by Alexander Tishchenko, Daniel D. Azorín, Laia Vidal-Brime, María José Muñoz, Pol Jiménez Arenas, Christopher Pearce, Henrique Girao, Santiago Ramón y Cajal and Trond Aasen
Cancers 2020, 12(10), 2798; https://doi.org/10.3390/cancers12102798 - 29 Sep 2020
Cited by 38 | Viewed by 6106
Abstract
Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and [...] Read more.
Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer. Full article
(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)
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Review

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22 pages, 396 KiB  
Review
Intercellular Communication in the Brain through Tunneling Nanotubes
by Khattar E. Khattar, Janice Safi, Anne-Marie Rodriguez and Marie-Luce Vignais
Cancers 2022, 14(5), 1207; https://doi.org/10.3390/cancers14051207 - 25 Feb 2022
Cited by 24 | Viewed by 5084
Abstract
Intercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells communicate with each other through several modalities, including paracrine [...] Read more.
Intercellular communication is essential for tissue homeostasis and function. Understanding how cells interact with each other is paramount, as crosstalk between cells is often dysregulated in diseases and can contribute to their progression. Cells communicate with each other through several modalities, including paracrine secretion and specialized structures ensuring physical contact between them. Among these intercellular specialized structures, tunneling nanotubes (TNTs) are now recognized as a means of cell-to-cell communication through the exchange of cellular cargo, controlled by a variety of biological triggers, as described here. Intercellular communication is fundamental to brain function. It allows the dialogue between the many cells, including neurons, astrocytes, oligodendrocytes, glial cells, microglia, necessary for the proper development and function of the brain. We highlight here the role of TNTs in connecting these cells, for the physiological functioning of the brain and in pathologies such as stroke, neurodegenerative diseases, and gliomas. Understanding these processes could pave the way for future therapies. Full article
(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)
21 pages, 2481 KiB  
Review
Specialized Intercellular Communications via Tunnelling Nanotubes in Acute and Chronic Leukemia
by Alessandro Allegra, Mario Di Gioacchino, Gabriella Cancemi, Marco Casciaro, Claudia Petrarca, Caterina Musolino and Sebastiano Gangemi
Cancers 2022, 14(3), 659; https://doi.org/10.3390/cancers14030659 - 28 Jan 2022
Cited by 12 | Viewed by 3316
Abstract
Effectual cell-to-cell communication is essential to the development and differentiation of organisms, the preservation of tissue tasks, and the synchronization of their different physiological actions, but also to the proliferation and metastasis of tumor cells. Tunneling nanotubes (TNTs) are membrane-enclosed tubular connections between [...] Read more.
Effectual cell-to-cell communication is essential to the development and differentiation of organisms, the preservation of tissue tasks, and the synchronization of their different physiological actions, but also to the proliferation and metastasis of tumor cells. Tunneling nanotubes (TNTs) are membrane-enclosed tubular connections between cells that carry a multiplicity of cellular loads, such as exosomes, non-coding RNAs, mitochondria, and proteins, and they have been identified as the main participants in healthy and tumoral cell communication. TNTs have been described in numerous tumors in in vitro, ex vivo, and in vivo models favoring the onset and progression of tumors. Tumor cells utilize TNT-like membranous channels to transfer information between themselves or with the tumoral milieu. As a result, tumor cells attain novel capabilities, such as the increased capacity of metastasis, metabolic plasticity, angiogenic aptitude, and chemoresistance, promoting tumor severity. Here, we review the morphological and operational characteristics of TNTs and their influence on hematologic malignancies’ progression and resistance to therapies, focusing on acute and chronic myeloid and acute lymphoid leukemia. Finally, we examine the prospects and challenges for TNTs as a therapeutic approach for hematologic diseases by examining the development of efficient and safe drugs targeting TNTs. Full article
(This article belongs to the Special Issue The Role of Tunneling Nanotubes in Intercellular Communication and Pathophysiology of Cancer)
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