A Multicellular Mechanochemical Model to Investigate Tumor Microenvironment Remodeling and Pre-Metastatic Niche Formation.

IF 2.3 4区医学 Q3 BIOPHYSICS

Cellular and molecular bioengineering Pub Date : 2024-11-13 eCollection Date: 2024-12-01 DOI:10.1007/s12195-024-00831-0

Shreyas U Hirway, Kylie G Nairon, Aleksander Skardal, Seth H Weinberg

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引用次数: 0

Abstract

Introduction: Colorectal cancer (CRC) is a major cause of cancer related deaths in the United States, with CRC metastasis to the liver being a common occurrence. The development of an optimal metastatic environment is essential process prior to tumor metastasis. This process, called pre-metastatic niche (PMN) formation, involves activation of key resident liver cells, including fibroblast-like stellate cells and macrophages such as Kupffer cells. Tumor-mediated factors introduced to this environment transform resident cells that secrete additional growth factors and remodel the extracellular matrix (ECM), which is thought to promote tumor colonization and metastasis in the secondary environment.

Methods: To investigate the underlying mechanisms of these dynamics, we developed a multicellular computational model to characterize the spatiotemporal dynamics of the PMN formation in tissue. This modeling framework integrates intracellular and extracellular signaling, and traction and junctional forces into a Cellular Potts model, and represents multiple cell types with varying levels of cellular activation. We perform numerical experiments to investigate the role of key factors in PMN formation and tumor invasiveness, including growth factor concentration, timing of tumor arrival, relative composition of resident cells, and the size of invading tumor cluster.

Results: These parameter studies identified growth factor availability and ECM concentration in the environment as two of the key determinants of tumor invasiveness. We further predict that both the ECM concentration potential and growth factor sensitivity of the stellate cells are key drivers of the PMN formation and associated ECM concentration.

Conclusions: Overall, this modeling framework represents a significant step towards simulating cancer metastasis and investigating the role of key factors on PMN formation.

Supplementary information: The online version contains supplementary material available at 10.1007/s12195-024-00831-0.

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.