PCOMPBIOL-D-25-00500

Exploring the relationship between vascular remodelling and tumour growth using agent-based modelling

PLOS Computational Biology

Dear Dr. Fan,

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Feilim Mac Gabhann, Ph.D.

Editor-in-Chief

PLOS Computational Biology

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

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Reviewer #1: Solid stresses produced by cancer cell growth in a confined space can compress blood and lymphatic vessels, but the details of the mechanical interactions between cells and structures are poorly understood. Here, the authors present a multiscale agent-based model (ABM) that simulates the mechanical interactions between proliferating tumor cells and vasculature. The authors show how tissue mechanics affect oxygen delivery and vessel remodeling, and conclude that vascular remodeling determines treatment response and post-radiotherapy regrowth.

In general, the study supports well-established findings or previous modeling work regarding the effects of solid stresses. The main innovation is the inclusion of realistic mechanical considerations in an AB model. The assumptions used in the development of the model appear to be sound in terms of the treatment of cell metabolism, cell-cell mechanics and vascular remodeling. I found the model a refreshing departure from the usual continuous models, and believe that such models are more useful for studying tumor heterogeneity. I have a few suggestions for improving the presentation of the study:

Comments:

1) Especially in the introduction, it would be important to make it clear that "pressure" refers to solid pressure, or solid stress, and that fluid pressure is not considered in the model.

2) The authors should clarify what happens at the tumor boundary. Do the cells there experience less friction, or is the constraint imposed by surrounding tissue being represented somehow?

3) An outstanding question in the field relates to how solid stresses are affected by cell invasion (see, e.g. https://doi.org/10.1038/s41551-018-0334-7). Can the model be modified to include active cell migration to address this question?

4) The inclusion of both the drag force and the friction force is confusing. Once the cell is moving, how do these differ, and are they both necessary? Also, Figure 1b could be more detailed to clarify how the friction force is working in the different regimes (stuck vs. moving).

5) Such a model would be straightforward to extend to 3D. The authors should comment on the potential limitations of the 2D simulations.

Reviewer #2: This manuscript presents a novel agent-based computational model of interactions between proliferating tumor cells and the tumor vasculature, focusing on the mechanical forces that are exerted to drive vessel occlusion and pruning due to compression. It also accounts for new vessel growth in response to hypoxia. The model makes novel and non-intuitive predictions about friction forces that represent adhesion between cells and the extracellular matrix. They also predict how dynamics of tumor growth and microvessel remodeling influence response to radiotherapy.

Overall, this is a well written paper that explores interesting biophysical/biomechanical cell-cell and cell-matrix interactions that haven’t yet been evaluated with multi-cell agent-based models. The purpose of the model is well justified, and the model methodology is described in sufficient detail. The quantification of complex spatial structures generated by the agent-based model through the use of spatial statistics is particularly innovative and reveal interesting and important details about tumor and tumor vasculature adaptations over time. I think the paper would be substantially strengthened by making at least a minor attempt at independent model validation by comparison of model predictions to published experimental data. Also, I have some minor comments and questions for the author’s consideration:

1. Methods: Regarding the model’s approximation of “Dynamic Oxygen Supply”, while varying vessel diameters are accounted for, how are the authors accounting for the fact that arterioles, capillaries, and venules contain blood whose oxygen tensions (i.e. P02) differ?

2. Methods: For the “Occlusion, Pruning and Angiogenesis”, the authors are not accounting for the connectivity of the vasculature, such that if one vessels is occluded or pruned, it is likely that nearby “collateral” blood vessels (that are connected to the same upstream parent vessel as the occluded vessel) would experience increased blood flow, and they could dynamically alter their diameter, as a result. In the Discussion, the authors briefly mention this model limitation as a potential opportunity for future model extension, but it would be helpful to also state this important model assumption in the description of the model in the Methods section when it is first described.

3. Methods: It is not clear why each simulation starts with 600 pruned vessels. One would assume that if there are only 4 tumor cells present initially, most if not all of the vessels would be “healthy”.

4. Results: in 3.3 the authors explore how ωh, the threshold oxygen concentration below which cells halt proliferation and become quiescent), affects tumor size, composition and morphology. With lower ωh values, cells can withstand lower oxygen concentrations and remain viable at greater distances from blood vessels, leading to a compact tumor mass. Whereas with higher ωh values, tumor cells are restricted to grow around the perfused blood vessels. They quantify the resulting tumor shape using a roundness score. It would seem that this prediction might be one that has (or could be) quantified in experimental or patient-derived pathology. Validation of this prediction by comparison to existing, publicly available data would strengthen the impact of this discovery.

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Reviewer #1: Yes

Reviewer #2: None

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Reviewer #1: No

Reviewer #2: No

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Dear Mr Fan,

We are pleased to inform you that your manuscript 'Exploring the relationship between vascular remodelling and tumour growth using agent-based modelling' has been provisionally accepted for publication in PLOS Computational Biology.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology.

Best regards,

Feilim Mac Gabhann, Ph.D.

Editor-in-Chief

PLOS Computational Biology

Feilim Mac Gabhann

Editor-in-Chief

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have sufficiently addressed my concerns.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

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Reviewer #1: No