3131 Oncostreams: Novel Dynamics Pathological Multicellular Structures Involved in Glioblatoma Growth and Invasion

Comba, Andrea; Dunn, Patrick; Argento, Anna E; Kadiyala, Padma; Motsch, Sébastien; Kish, Phillip E.; Kahana, Alon; Zamler, Daniel B.; Muraszko, Karin M.; Castro, Maria G.; Löwenstein, Pedro R.

doi:10.1017/cts.2019.253

Cited by 4 publications

(4 citation statements)

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“…Anti-migratory effect of ST-401 would also inhibit the malignant repair response that follows surgeries, which is of potential clinical relevance since currently there are no such therapies available. 10 , 34 , 35 As such, MT function play a central role in glioma migration and their dismantling by MTA that disrupt the cell migration machinery, cell morphology, and overall dynamics of growing tumors has emerged as a promising therapeutic approach for the treatment of glioma. 31 …”

Section: Discussionmentioning

confidence: 99%

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Horne

Diaz

Cimino

et al. 2020

Neuro-Oncology Advances

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Background Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. Methods Synthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model. Results We discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT). Conclusion Our study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs.

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Section: Discussionmentioning

confidence: 99%

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Horne

Diaz

Cimino

et al. 2020

Neuro-Oncology Advances

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“…Most of our experimental work was performed using mouse tissues and genetically engineered mouse models of brain tumors. However, the recognition of oncostreams in human malignant gliomas [35] strongly suggests that human brain tumors can also self-organize into structures that influence tumor malignity. We suggest that a novel approach to the treatment of brain tumors was to disassemble the oncostreams.…”

Section: Plos Computational Biologymentioning

confidence: 99%

Self-organization in brain tumors: How cell morphology and cell density influence glioma pattern formation

et al. 2020

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Modeling cancer cells is essential to better understand the dynamic nature of brain tumors and glioma cells, including their invasion of normal brain. Our goal is to study how the morphology of the glioma cell influences the formation of patterns of collective behavior such as flocks (cells moving in the same direction) or streams (cells moving in opposite direction) referred to as oncostream. We have observed experimentally that the presence of oncostreams correlates with tumor progression. We propose an original agent-based model that considers each cell as an ellipsoid. We show that stretching cells from round to ellipsoid increases stream formation. A systematic numerical investigation of the model was implemented in R 2. We deduce a phase diagram identifying key regimes for the dynamics (e.g. formation of flocks, streams, scattering). Moreover, we study the effect of cellular density and show that, in contrast to classical models of flocking, increasing cellular density reduces the formation of flocks. We observe similar patterns in R 3 with the noticeable difference that stream formation is more ubiquitous compared to flock formation.

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“…The 339 identification of multicellular structures in brain tumors suggest that single cells are 340 able to coalesce into multicellular patterns, possibly as a result of self-organization. We 341 have recently described such multicellular structures within gliomas [11]. As these 342 structures are reminiscent of streams described in other systems, we have labeled these 343 structures oncostreams.…”

Section: Conclusion 338mentioning

confidence: 99%

Self-organization in brain tumors: how cell morphology and cell density influence glioma pattern formation

Jamous

Comba

Löwenstein

et al. 2019

Preprint

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AbstractModeling cancer cells is essential to better understand the dynamic nature of brain tumors and glioma cells, including their invasion of normal brain. Our goal is to study how the morphology of the glioma cell influences the formation of patterns of collective behavior such as flocks (cells moving in the same direction) or streams (cells moving in opposite direction) referred to as oncostream. We have observed experimentally that the presence of oncostreams correlates with tumor progression. We propose an original agent-based model that considers each cell as an ellipsoid. We show that stretching cells from round to ellipsoid increases stream formation.A systematic numerical investigation of the model was implemented in ℝ2. We deduce a phase diagram identifying key regimes for the dynamics (e.g. formation of flocks, streams, scattering). Moreover, we study the effect of cellular density and show that, in contrast to classical models of flocking, increasing cellular density reduces the formation of flocks. We observe similar patterns in ℝ3 with the noticeable difference that stream formation is more ubiquitous compared to flock formation.Author summarySelf-organization is the formation of large-scale multicellular patterns that result exclusively from the interactions amongst constituent single cells. To establish the existence of self-organization in brain tumors we used agent-based modeling based on data extracted from static and dynamic genetically engineered mouse glioma models. Implementation of our model in ℝ2 identifies the dynamics that lead to formation of flocks (cells moving in a single direction), streams (cells moving in two directions), and cells moving as swarms or scattering. Increasing cellular density reduced formation of flocks and increased the formation of streams both in ℝ2 and in ℝ3. These results demonstrate the detailed mechanism leading to self-organization in brain tumors. As increasing density of oncostreams correlates with tumor malignancy, we establish a pathophysiological link between self-organization of glioma tumors and glioma malignancy. We propose the dismantling of oncostreams as a new therapeutic approach to the treatment of brain tumors.

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3131 Oncostreams: Novel Dynamics Pathological Multicellular Structures Involved in Glioblatoma Growth and Invasion

Cited by 4 publications

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A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Self-organization in brain tumors: How cell morphology and cell density influence glioma pattern formation

Self-organization in brain tumors: how cell morphology and cell density influence glioma pattern formation

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