Role of Mechanotransduction in Cancer: A Complex Problem Involving Gene Mutations and Altered Levels of Connection Components

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The term "energy storage" is repeatedly used throughout the manuscript; however, its exact meaning is not clearly defined. Since this concept represents one of the central elements of the proposed hypothesis, I recommend providing a concise explanation in the Introduction to clarify what is meant by energy storage in the context of mechanotransduction.
2. The manuscript provides a comprehensive overview of the molecules involved in mechanotransduction. While this extensive background information is valuable, it also makes it difficult for readers to visualize how these molecules converge into the proposed mechanistic pathway. I recommend including a final schematic illustration that integrates the key molecules, signaling pathways, and proposed sequence of events into a single conceptual figure.
3. The Conclusion would be strengthened by discussing the potential implications of this hypothesis for cancer therapy. Specifically, the authors could elaborate on how validating this hypothesis may contribute to addressing important challenges such as drug delivery, tumor angiogenesis, cancer cell migration, metastasis, and the development of novel therapeutic strategies.
4. As this is presented as a hypothesis paper, I encourage the authors to include a brief section discussing how the proposed hypothesis could be experimentally validated. In particular, which in vitro, in vivo, or biomechanical approaches would be most appropriate for testing the proposed mechanotransduction model?

Author Response

Thank you for your comments on the model presented in this manuscript. We have revised the paper to consider these points in detail.

1. The term "energy storage" is repeatedly used throughout the manuscript; however, its exact meaning is not clearly defined. Since this concept represents one of the central elements of the proposed hypothesis, I recommend providing a concise explanation in the Introduction to clarify what is meant by energy storage in the context of mechanotransduction.

The paper has been revised to more clearly point out that when a force is placed on a material and it undergoes a deformation (force through a distance) work is done which is energy that is applied to the tissue. The energy must be absorbed, transmitted, or dissipated within the tissue; mechanical forces cause energy to be created and therefore upregulate mechanotransduction

1. The manuscript provides a comprehensive overview of the molecules involved in mechanotransduction. While this extensive background information is valuable, it also makes it difficult for readers to visualize how these molecules converge into the proposed mechanistic pathway. I recommend including a final schematic illustration that integrates the key molecules, signaling pathways, and proposed sequence of events into a single conceptual figure.

We have revised the legend in Figure 8 to include some of this information to provide more clarity.

1. The Conclusion would be strengthened by discussing the potential implications of this hypothesis for cancer therapy. Specifically, the authors could elaborate on how validating this hypothesis may contribute to addressing important challenges such as drug delivery, tumor angiogenesis, cancer cell migration, metastasis, and the development of novel therapeutic strategies.

The discussion has been modified to discuss how this information affects cancer. Since there are so many different molecules that are affected and cancer is so complex there is no simple answer at this point

1. As this is presented as a hypothesis paper, I encourage the authors to include a brief section discussing how the proposed hypothesis could be experimentally validated. In particular, which in vitro, in vivo, or biomechanical approaches would be most appropriate for testing the proposed mechanotransduction model?

The manuscript has been revised to reflect our experimental studies in vivo on skin cancer which discuss the effects of increased cell and collagen stiffness.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled Role of Mechanotransduction in Cancer: A Complex Multifactorial Problem Involving Gene Mutations and Altered Levels of Connection Components, presents an interesting hypothesis concerning the contribution of mechanical forces, energy transmission, and alterations in cellular and extracellular connections to cancer development and progression. The manuscript addresses a scientifically important and increasingly relevant area of cancer biology by integrating genetic mutations, extracellular matrix remodeling, cytoskeletal alterations, cellular adhesion, and mechanotransduction signaling pathways within a unified conceptual framework.

 

Major comments

The manuscript is presented as a hypothesis article, but some sections resemble a narrative review. The authors should clearly define the article type, objectives, and scope at the end of the Introduction. A concise statement distinguishing established findings from the novel hypothesis proposed in this manuscript is required.

The hypothesis that disruption of mechanical connections causes local stress and energy concentrations, which subsequently alter mechanotransduction pathways and promote cancer-related changes, is interesting but remains insufficiently developed. The authors should explain more clearly:

• How local mechanical stress and energy concentrations are generated and measured;
• How these changes initiate or modify EMT and endothelial-to-mesenchymal transition;
• How excess energy is proposed to alter myosin or other motor proteins;
• Which elements of the proposed mechanism are supported experimentally and which remain speculative.

Reference 8 is described as a manuscript submitted for publication. Because the multiscale mechanical model is central to the present paper, an unpublished and inaccessible source should not serve as its primary foundation. The authors should either replace it with published evidence or provide a sufficiently detailed and self-contained explanation of the model within the current manuscript.

Repetitive descriptions should be reduced, and each molecular subsection should explicitly explain how the discussed component supports the proposed hypothesis.

The reference list requires comprehensive revision. Reference number 28 is used twice, which appears to have caused mismatches between subsequent in-text citations and bibliography entries. All citations following this duplication must be checked and renumbered. The authors should also:

The manuscript requires careful English-language editing. There are grammatical errors, typographical problems, inconsistent capitalization, incomplete sentences, and inconsistent use of technical terms. Examples include inconsistent forms of “overexpression,” “underexpression,” “β-catenin,” “c-SRC,” “COL11A1,” and mechanotransduction-related terminology. Professional language revision is recommended.

 

Minor comments

1. Revise the title for clarity and concision.
2. Rewrite the abstract to clearly present the background, purpose, conceptual approach, principal hypothesis, and implications.
3. Clarify that no new experimental data were generated or analyzed.
4. Avoid causal language where the cited evidence demonstrates only an association.
5. Include a brief section proposing experimental approaches to test the hypothesis, such as matrix-stiffness models, traction-force microscopy, mechanical loading experiments, live-cell tension sensors, or targeted disruption of focal-adhesion components.

 

Author Response

We thank the reviewer for their helpful comments and respond below point by point.
Comments and Suggestions for Authors

The manuscript entitled Role of Mechanotransduction in Cancer: A Complex Multifactorial Problem Involving Gene Mutations and Altered Levels of Connection Components, presents an interesting hypothesis concerning the contribution of mechanical forces, energy transmission, and alterations in cellular and extracellular connections to cancer development and progression. The manuscript addresses a scientifically important and increasingly relevant area of cancer biology by integrating genetic mutations, extracellular matrix remodeling, cytoskeletal alterations, cellular adhesion, and mechanotransduction signaling pathways within a unified conceptual framework.

 

Major comments

The manuscript is presented as a hypothesis article, but some sections resemble a narrative review. The authors should clearly define the article type, objectives, and scope at the end of the Introduction. A concise statement distinguishing established findings from the novel hypothesis proposed in this manuscript is required.

The manuscript has been revised to more clearly state the goal of the paper.

The hypothesis that disruption of mechanical connections causes local stress and energy concentrations, which subsequently alter mechanotransduction pathways and promote cancer-related changes, is interesting but remains insufficiently developed. The authors should explain more clearly:

• How local mechanical stress and energy concentrations are generated and measured;

This point has been addressed.

• How these changes initiate or modify EMT and endothelial-to-mesenchymal transition;
• Effects of EMT and ENT have been addressed in the revised paper.
• Effects of How excess energy is proposed to alter myosin or other motor proteins;
• The paper discusses the dissipation of allied mechanical energy via myosin in the paper. The effects of the other motor proteins is beyond the scope of the model.
• Which elements of the proposed mechanism are supported experimentally and which remain speculative.
• The experimental results from in vivo skin cancer studies have been emphasized in the revised manuscript.

Reference 8 is described as a manuscript submitted for publication. Because the multiscale mechanical model is central to the present paper, an unpublished and inaccessible source should not serve as its primary foundation. The authors should either replace it with published evidence or provide a sufficiently detailed and self-contained explanation of the model within the current manuscript.

The model is described in more detail in the revised manuscript.

Repetitive descriptions should be reduced, and each molecular subsection should explicitly explain how the discussed component supports the proposed hypothesis.

A better transition between subsections has been added.

The reference list requires comprehensive revision. Reference number 28 is used twice, which appears to have caused mismatches between subsequent in-text citations and bibliography entries. All citations following this duplication must be checked and renumbered. The authors should also:

Thank you for your observation.

The manuscript requires careful English-language editing. There are grammatical errors, typographical problems, inconsistent capitalization, incomplete sentences, and inconsistent use of technical terms. Examples include inconsistent forms of “overexpression,” “underexpression,” “β-catenin,” “c-SRC,” “COL11A1,” and mechanotransduction-related terminology. Professional language revision is recommended.

Thank you for pointing out these problems.

 

Minor comments

1. Revise the title for clarity and concision.
2. Rewrite the abstract to clearly present the background, purpose, conceptual approach, principal hypothesis, and implications.
3. Clarify that no new experimental data were generated or analyzed.
4. Avoid causal language where the cited evidence demonstrates only an association.
5. Include a brief section proposing experimental approaches to test the hypothesis, such as matrix-stiffness models, traction-force microscopy, mechanical loading experiments, live-cell tension sensors, or targeted disruption of focal-adhesion components.

These comments have been addressed in the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This is an interesting paper (review) of hypothesis.

The author aims to demonstrate that changes in gene and protein expression within the linkage between the extracellular matrix (ECM) and associated cells alter energy storage and dissipation, thereby driving tumor formation. This hypothesis was tested by examining mutations in various proteins—such as those of the cytoskeleton—that interact mechanically with the ECM. While the experiments and analyses have been carefully conducted, please address only one question:

 

Uncontrolled proliferation is a defining characteristic of tumors. While ECM-related mutations successfully recapitulate many properties of tumor cells, they appear unable to reproduce the increased proliferation rate. Mutations in p53 and TGF-β seem to be required, yet these are not mechanotransduction-related genes; this fact contradicts the hypothesis. Please explain this in the main text.

 

Author Response

The author aims to demonstrate that changes in gene and protein expression within the linkage between the extracellular matrix (ECM) and associated cells alter energy storage and dissipation, thereby driving tumor formation. This hypothesis was tested by examining mutations in various proteins—such as those of the cytoskeleton—that interact mechanically with the ECM. While the experiments and analyses have been carefully conducted, please address only one question:

 

Uncontrolled proliferation is a defining characteristic of tumors. While ECM-related mutations successfully recapitulate many properties of tumor cells, they appear unable to reproduce the increased proliferation rate. Mutations in p53 and TGF-β seem to be required, yet these are not mechanotransduction-related genes; this fact contradicts the hypothesis. Please explain this in the main text.

 Thank you for this question since it is very relevant. The role of TGF-beta in EMT and cancer cell proliferation is very important and involves mechanotransduction pathways. The next phase of this model is to integrate the changes associated with EMT and TGF-beta and mechanotransduction as well as to look at the effect of other mutations that have been documented. This information has been added to the revised paper.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

It is acceptable now