Research Article: Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma

Date Published: October 4, 2018

Publisher: Public Library of Science

Author(s): Yangjin Kim, Hyunji Kang, Gibin Powathil, Hyeongi Kim, Dumitru Trucu, Wanho Lee, Sean Lawler, Mark Chaplain, Dominik Wodarz.


The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical cues in the microenvironment. Recent studies have shown that miR-451 regulates downstream molecules including AMPK/CAB39/MARK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of the main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this complex process of cell proliferation and invasion and its response to conventional treatment, we propose a mathematical model that analyzes the intracellular dynamics of the miR-451-AMPK- mTOR-cell cycle signaling pathway within a cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress in response to fluctuating glucose levels. We show how up- or down-regulation of components in these pathways affects the key cellular decision to infiltrate or proliferate in a complex microenvironment in the absence and presence of time delays and stochastic noise. Glycosylated chondroitin sulfate proteoglycans (CSPGs), a major component of the extracellular matrix (ECM) in the brain, contribute to the physical structure of the local brain microenvironment but also induce or inhibit glioma invasion by regulating the dynamics of the CSPG receptor LAR as well as the spatiotemporal activation status of resident astrocytes and tumor-associated microglia. Using a multi-scale mathematical model, we investigate a CSPG-induced switch between invasive and non-invasive tumors through the coordination of ECM-cell adhesion and dynamic changes in stromal cells. We show that the CSPG-rich microenvironment is associated with non-invasive tumor lesions through LAR-CSGAG binding while the absence of glycosylated CSPGs induce the critical glioma invasion. We illustrate how high molecular weight CSPGs can regulate the exodus of local reactive astrocytes from the main tumor lesion, leading to encapsulation of non-invasive tumor and inhibition of tumor invasion. These different CSPG conditions also change the spatial profiles of ramified and activated microglia. The complex distribution of CSPGs in the tumor microenvironment can determine the nonlinear invasion behaviors of glioma cells, which suggests the need for careful therapeutic strategies.

Partial Text

Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is characterized by rapid proliferation and aggressive invasion [1]. Poor clinical outcomes of glioblastoma are due to aggressive brain infiltration, driven in part by microRNA-mediated alterations in protein levels [2], leading to inevitable recurrence after surgery [3]. Conventional treatment methods such as surgery, primary treatment method, radiotherapy and chemotherapy have not proven to be effective [4] for this aggressive disease with a median survival time of approximately 15 months from the time of diagnosis [5–7]. In particular, invasive GBM cells, described as “guerrilla-like warriors”, can escape surgery and are protected behind the blood-brain barrier (BBB) and survive biochemical attacks from chemotherapy [8, 9]. Innovative new therapeutic approaches to block these invasive cells are needed in order to improve clinical outcome [10].

Consider brain tissue, Ω = [0, L] × [0, L], with a tumor initially occupying a sphere, and astrocytes and ramified/activated microglia in the tumor microenvironment. A tumor cell either proliferates or migrates under certain biochemical conditions of miR-451-AMPK-mTOR-cell cycle activation and biomechanical binding to ECM from LAR-CSGAG regulation in response to nutrients (oxygen and glucose) and CSPG ECM according to the reaction-diffusion model. While mechanical movement of the tumor cell, astrocytes, and microglia is governed by the cell-based mechanical model, their migration direction is influenced by random motility and chemotaxis. On the other hand, the dynamics in the reaction-diffusion model depend on individual-cell components. A schematic of the hybrid model is shown in Fig 2. The multi-scale hybrid model contains the following components: (1) intracellular signaling pathway of a tumor cell (miR-451-AMPK-mTOR-cell cycle, LAR-CSGAG), (2) cell-based mechanical model (tumor cell, astrocytes, microglia), (3) reaction-diffusion model of extracellular biochemical players (oxygen, glucose, CSPG, Chase-ABC). In the next section, we introduce an intracellular model of cell proliferation and migration via miR-451-AMPK-mTOR-cell cycle.




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