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

Oncology Medicine Life Sciences Bioengineering Cell Biology
Tumor Microenvironment Pre-Metastatic Niche Computational Modeling Epithelial-Mesenchymal Transition Tumor Cells Kupffer Cells Stellate Cells

Colorectal Cancer (CRC) is one of the leading causes of cancer-related deaths in the United States, with liver metastasis being a common occurrence. Before tumor metastasis, the formation of the Pre-Metastatic Niche (PMN) is a critical process. PMN involves the activation of key liver-resident cells, including fibroblast-like stellate cells and macrophages (such as Kupffer cells). Tumor-derived factors alter these cells, causing them to secrete additional growth factors and remodel the Extracellular Matrix (ECM), thereby promoting tumor colonization and metastasis in the secondary environment. To better understand the mechanisms behind these dynamics, researchers developed a multicellular computational model to characterize the spatiotemporal dynamics of PMN formation.

Source of the Paper

This paper was co-authored by Shreyas U. Hirway, Kylie G. Nairon, Aleksander Skardal, and Seth H. Weinberg, all from the Department of Biomedical Engineering at The Ohio State University. The paper was published online on November 13, 2024, in the journal Cellular and Molecular Bioengineering.

Research Process

1. Model Construction

The researchers developed a multicellular computational model that integrates intracellular and extracellular signaling, traction forces, and junctional forces into a Cellular Potts Model (CPM). This model can represent multiple cell types and their varying levels of activation.

2. Numerical Experiments

The researchers conducted numerical experiments to explore 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 the invading tumor cluster.

3. Parameter Studies

The study investigated the impact of these parameters on tumor invasiveness by varying growth factor dosage, time before tumor entry, growth factor sensitivity of Kupffer and stellate cells, tumor cluster size, and the ratio of Kupffer to stellate cells.

4. Data Quantification

The study quantified multiple PMN metrics, including the average activation levels of Kupffer and stellate cells, ECM-localized growth factor concentration, average tumor cell activation, the number of connections between tumor and non-tumor cells, and the average distance between initially introduced tumor cells.

Key Findings

1. PMN Remodeling

During the PMN remodeling phase, the activation of stellate cells significantly increased ECM concentration, particularly in areas where stellate cells were highly activated. Kupffer cell activation also increased, but to a lesser extent.

2. Tumor Invasion

During the tumor entry phase, tumor cells remained highly activated in areas with high ECM concentration and migrated outward, forming connections with surrounding Kupffer and stellate cells. Over time, tumor cells proliferated and occupied most of the system space.

3. Growth Factor Dosage

Increasing growth factor dosage significantly enhanced ECM concentration and cell activation levels, especially at low doses. However, beyond 2-3 μM, the median values of these metrics tended to stabilize.

4. Tumor Cluster Size

Larger tumor clusters exhibited lower tumor cell activation levels upon entry, but higher tumor invasiveness, as indicated by more non-tumor cell connections and earlier increases in the distance between tumor cells.

5. Kupffer and Stellate Cell Ratio

Increasing the proportion of stellate cells significantly increased ECM concentration and cell activation levels, particularly when the stellate cell proportion exceeded 30%, leading to significantly higher tumor invasiveness.

Conclusion

The multicellular model developed in this study can simulate the cellular and tissue-level dynamics of PMN formation and tumor invasion. Through parameter studies, the researchers revealed the impact of key factors such as growth factors, ECM concentration, and stellate cell proportion on tumor invasiveness. This model provides an important tool for understanding the mechanisms of tumor metastasis and offers new directions for future cancer therapy research.

Research Highlights

  1. Multicellular Model: This study is the first to integrate multiple cell types (Kupffer cells, stellate cells, and tumor cells) into a single model, simulating the complex dynamics of PMN formation and tumor invasion.
  2. Integration of Mechanical and Chemical Signaling: The model not only considers mechanical interactions between cells but also integrates intracellular and extracellular chemical signaling, providing a more comprehensive simulation of the tumor microenvironment.
  3. Parameter Studies: Systematic parameter studies revealed key factors influencing tumor invasiveness, offering potential targets for future cancer therapies.

Additional Valuable Information

The model can be further expanded into a three-dimensional system and incorporate additional cell types and growth factors to more accurately simulate the tumor microenvironment. Additionally, the model can be used to study the dynamics of cancer therapy, such as evaluating the effects of anti-migratory drugs on tumor invasiveness.

This research not only provides new insights into the mechanisms of tumor metastasis but also offers important theoretical support for developing cancer therapy strategies targeting PMN. By simulating the complex dynamics of the tumor microenvironment, the researchers have opened new avenues for future cancer therapy research.