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An ecosystem mimicking brain development promotes metastatic growth of SCLC in the brain

ABSTRACT: Small cell lung cancer (SCLC) is a fatal form of cancer that frequently metastasizes to the brain. Here we investigated the mechanisms allowing SCLC cells to grow in the unique brain microenvironment. We found that neuronal programs upregulated in SCLC cells during tumor progression and upon growth in the brain are critical for SCLC growth in the brain. Mechanistically, the presence of SCLC cells in the brain re-activates astrocytes, which in turn promote the survival of SCLC cells by secreting neuronal pro-survival factors such as SERPINE1. We also identified Reelin, a molecule produced by developing neurons to recruit astrocytes, as a molecule secreted by SCLC cells to recruit astrocytes to the tumor site and promote SCLC growth in the brain. Thus, SCLC cells co-opt mechanisms normally at play between astrocytes and neurons to promote SCLC growth in the brain. Targeting such developmental neuronal programs may help treat brain metastases.

ORGANISM(S): Mus musculus

PROVIDER: GSE202233 | GEO | 2023/08/09

REPOSITORIES: GEO

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Project description:Cloutier2009 - Brain Energy Metabolism This model was taken from the CellML repository and automatically converted to SBML. Following the submission the parameters are manually encoded and annotated as spices and global quantities by BioModels curators. The original model was: Cloutier M, Bolger FB, Lowry JP, Wellstead P. (2009) - version=1.0 The original CellML model was created by: Catherine Lloyd c.lloyd@auckland.ac.nz The University of Auckland This model is described in the article: An integrative dynamic model of brain energy metabolism using in vivo neurochemical measurements. Cloutier M, Bolger FB, Lowry JP, Wellstead P. J Comput Neurosci 2009 Dec; 27(3): 391-414 Abstract: An integrative, systems approach to the modelling of brain energy metabolism is presented. Mechanisms such as glutamate cycling between neurons and astrocytes and glycogen storage in astrocytes have been implemented. A unique feature of the model is its calibration using in vivo data of brain glucose and lactate from freely moving rats under various stimuli. The model has been used to perform simulated perturbation experiments that show that glycogen breakdown in astrocytes is significantly activated during sensory (tail pinch) stimulation. This mechanism provides an additional input of energy substrate during high consumption phases. By way of validation, data from the perfusion of 50 microM propranolol in the rat brain was compared with the model outputs. Propranolol affects the glucose dynamics during stimulation, and this was accurately reproduced in the model by a reduction in the glycogen breakdown in astrocytes. The model's predictive capacity was verified by using data from a sensory stimulation (restraint) that was not used for model calibration. Finally, a sensitivity analysis was conducted on the model parameters, this showed that the control of energy metabolism and transport processes are critical in the metabolic behaviour of cerebral tissue. This model is hosted on BioModels Database and identified by: BIOMD0000000554. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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An ecosystem mimicking brain development promotes metastatic growth of SCLC in the brain

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