Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas

Weil, Sophie; Osswald, Matthias; Solecki, Gergely; Grosch, Julia; Jung, Eui-Man; Lemke, Dieter; Ratliff, Miriam; Hänggi, Daniel; Wick, Wolfgang; Winkler, Frank

doi:10.1093/neuonc/nox070

Cited by 193 publications

(233 citation statements)

References 48 publications

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“…Surgical resection of GBM tumors is rarely complete because the tumor aggressively infiltrates the brain, with cells interconnecting via long membrane protrusions (microtubes) 4 . The resulting network enables multicellular communication through microtube-associated gap junctions, and increases tumor resistance to cell ablation and radiotherapy 5 . Moreover, glioblastoma cells interact with normal brain cells via soluble factors or direct cell-cell contacts to promote tumor proliferation and invasion 6 .…”

Section: Introductionmentioning

confidence: 99%

Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics

Krieger

Tirier

Park

et al. 2019

Preprint

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AbstractGlioblastoma multiforme (GBM) are devastating neoplasms with high invasive capacity. GBM has been difficult to study in vitro. Therapeutic progress is also limited by cellular heterogeneity within and between tumors. To address these challenges, we present an experimental model using human cerebral organoids as a scaffold for patient-derived glioblastoma cell invasion. By tissue clearing and confocal microscopy, we show that tumor cells within organoids extend a network of long microtubes, recapitulating the in vivo behavior of GBM. Single-cell RNA-seq of GBM cells before and after co-culture with organoid cells reveals transcriptional changes implicated in the invasion process that are coherent across patient samples, indicating that GBM cells reactively upregulate genes required for their dispersion. Functional therapeutic targets are identified by an in silico receptor-ligand pairing screen detecting potential interactions between GBM and organoid cells. Taken together, our model has proven useful for studying GBM invasion and transcriptional heterogeneity in vitro, with applications for both pharmacological screens and patient-specific treatment selection at a time scale amenable to clinical practice.

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Section: Introductionmentioning

confidence: 99%

Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics

Krieger

Tirier

Park

et al. 2019

Preprint

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“…Our finding that TMTs are present in the pancreatic tumor environment agrees with previous observations in several tumor types (Lou et al, 2012;Osswald et al, 2015;Griessinger et al, 2017;Desir et al, 2018). One function of TMTs is to provide resistance to radiation, chemotherapy, or other assaults (Osswald et al, 2015;Weil et al, 2017;Desir et al, 2018). Interestingly, we can only identify clear TMTs in a sub-set of primary tumor samples.…”

Section: Discussionmentioning

confidence: 99%

“…In a glioblastoma model, IMTs of > 100 m extended at the invasive edge of the tumor into peripheral tissue. These IMTs had a diameter ~1.6 m, contained both actin and microtubules, and correlated with increased resistance to radiation and chemotherapy (Osswald et al, 2015;Weil et al, 2017). Similarly, IMTs that contribute to treatment resistance have been identified in pancreatic cancer (Desir et al, 2018), prostate cancer (Kretschmer et al, 2019), mesothelioma (Lou et al, 2012) and leukemias (Polak et al, 2015).…”

Section: Introductionmentioning

confidence: 95%

Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner

Latario

Schoenfeld

Howarth

et al. 2019

Preprint

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Actin-based tubular connections between cells have been observed in many cell types. Termed "tunneling nanotubes (TNTs)", "membrane nanotubes", "tumor microtubes (TMTs)", or "cytonemes", these protrusions interconnect cells in dynamic networks. Structural features in these protrusions vary between cellular systems, including tubule diameter and presence of microtubules. We find tubular protrusions, which we classify as TMTs, in a pancreatic cancer cell line, DHPC-018. TMTs are present in DHPC-018-derived tumors in mice, as well as in a mouse model of pancreatic cancer and a sub-set of primary human tumors. DHPC-018 TMTs have heterogeneous diameter (0.39 -5.85 m, median 1.92 m) and contain actin filaments, microtubules, and cytokeratin 19-based intermediate filaments. The actin filaments are cortical within the protrusion, as opposed to TNTs, in which filaments run down the center of the tube. TMTs are dynamic in length, but are long-lived (median > 60 min). Inhibition of actin polymerization, but not microtubules, results in TMT loss. A second class of tubular protrusion, which we term cell-substrate protrusion (CSP), has similar width range and cytoskeletal features but make contact with the substratum as opposed to another cell. Similar to previous work on TNTs, we find two assembly mechanisms for TMTs, which we term "pull-away" and "search-andcapture".

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“…Furthermore, tumor microtubes are long‐lived, having been found to persist for months, and they can serve not only as a physical scaffold for invasion but also as a conduit for the propagation of intercellular calcium waves, thus allowing communication between distant tumor cells . They can also convey resistance to surgical lesions and chemotherapy …”

Section: Animal Models At Work: Current Research Topicsmentioning

confidence: 99%

Modeling phenotypes of malignant gliomas

Sampetrean

Saya

2017

Cancer Science

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Malignant gliomas are primary tumors of the central nervous system characterized by diffuse infiltration into the brain and a high recurrence rate. Advances in comprehensive genomic studies have provided unprecedented insight into the genetic and molecular heterogeneity of these tumors and refined our understanding of their evolution from low to high grade. However, similar levels of phenotypic characterization are indispensable to understanding the complexity of malignant gliomas. Experimental glioma models have also achieved great progress in recent years. Advances in transgenic technologies and cell culture have allowed the establishment of mouse models that mirror the human disease with increasing fidelity and which support single‐cell resolution for phenotypic analyses. Here we review the major types of preclinical glioma models, with an emphasis on how recent developments in experimental modeling have shed new light on two fundamental aspects of glioma phenotype, their cell of origin and their invasive potential.

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Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas

Abstract: TMs can contribute to the resistance against standard treatment modalities in gliomas. Specific inhibition of TMs is a promising approach to reduce local recurrence after surgery and lower resistance to chemotherapy.

Cited by 193 publications

References 48 publications

Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics

Modeling glioblastoma invasion using human brain organoids and single-cell transcriptomics

Tumor microtubes connect pancreatic cancer cells in an Arp2/3 complex-dependent manner

Modeling phenotypes of malignant gliomas

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