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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研究肿瘤微环境重塑和转移前生态位形成的多细胞机械化学模型。

导读：结直肠癌（CRC）是美国癌症相关死亡的主要原因，结直肠癌转移到肝脏是一种常见的现象。最佳转移环境的形成是肿瘤转移前必不可少的过程。这个过程被称为转移前生态位（PMN）的形成，涉及到关键的常驻肝细胞的激活，包括成纤维细胞样星状细胞和巨噬细胞，如Kupffer细胞。引入这种环境的肿瘤介导因子转化驻留细胞，分泌额外的生长因子并重塑细胞外基质（ECM），这被认为促进肿瘤在继发性环境中的定植和转移。方法：为了研究这些动态的潜在机制，我们开发了一个多细胞计算模型来表征组织中PMN形成的时空动态。该建模框架将细胞内和细胞外信号，牵引和连接力整合到Cellular Potts模型中，并代表具有不同细胞激活水平的多种细胞类型。我们通过数值实验来研究PMN形成和肿瘤侵袭的关键因素，包括生长因子浓度、肿瘤到达时间、驻留细胞的相对组成和侵袭肿瘤簇的大小。结果：这些参数研究确定生长因子可用性和环境中的ECM浓度是肿瘤侵袭性的两个关键决定因素。我们进一步预测，星状细胞的ECM浓度电位和生长因子敏感性是PMN形成和相关ECM浓度的关键驱动因素。结论：总的来说，该建模框架代表了模拟癌症转移和研究关键因素在PMN形成中的作用的重要一步。补充信息：在线版本包含补充资料，可在10.1007/s12195-024-00831-0获取。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.