Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts
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eLife assessment
This paper presents a series of experiments investigating the role of cadherin-11 mediated interactions between cancer cells and fibroblasts in metastasis using updated 3D cell co-invasion assays. The primarily descriptive data are a valuable contribution to our understanding of the nature of cross cell-type interactions in metastasis, but are incomplete with respect to the far-reaching conclusions about the central role cadherin-11, especially given the complex nature of the phenotype and the need to better contextualize these observations in a complete picture of metastasis.
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Abstract
Abstract
Current prevailing knowledge on EMT (epithelial mesenchymal transition) deems epithelial cells acquire the characters of mesenchymal cells to be capable of invading and metastasizing on their own. One of the signature events of EMT is called “cadherin switch”, e.g. the epithelial E-cadherin switching to the mesenchymal Cadherin-11. Here, we report the critical events after EMT that cancer cells utilize cadherin-11 to hijack the endogenous cadherin-11 positive fibroblasts. Numerous 3-D cell invasion assays with high-content live cell imaging methods reveal that cadherin-11 positive cancer cells adhere to and migrate back and forth dynamically on the cell bodies of fibroblasts. By adhering to fibroblasts for co-invasion through 3-D matrices, cancer cells acquire higher invasion speed and velocity, as well as significantly elevated invasion persistence, which are exclusive characteristics of fibroblast invasion. Silencing cadherin-11 in cancer cells or in fibroblasts, or in both, significantly decouples such physical co-invasion. Additional bioinformatics studies and PDX (patient derived xenograft) studies link such cadherin-11 mediated cancer hijacking fibroblasts to the clinical cancer progression in human such as triple-negative breast cancer patients. Further animal studies confirm cadherin-11 mediates cancer hijacking fibroblasts in vivo and promotes significant solid tumor progression and distant metastasis. Moreover, overexpression of cadherin-11 strikingly protects 4T1-luc cells from implant rejection against firefly luciferase in immunocompetent mice. Overall, our findings report and characterize the critical post-EMT event of cancer hijacking fibroblasts in cancer progression and suggest cadherin-11 can be a therapeutic target for solid tumors with stroma. Our studies hence provide significant updates on the “EMT” theory that EMT cancer cells can hijack fibroblasts to achieve full mesenchymal behaviors in vivo for efficient homing, growth, metastasis and evasion of immune surveillance. Our studies also reveal that cadherin-11 is the key molecule that helps link cancer cells to stromal fibroblasts in the “Seed & Soil” theory.
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Author Response
eLife assessment
This paper presents a series of experiments investigating the role of cadherin-11 mediated interactions between cancer cells and fibroblasts in metastasis using updated 3D cell co-invasion assays. The primarily descriptive data are a valuable contribution to our understanding of the nature of cross cell-type interactions in metastasis, but are incomplete with respect to the far-reaching conclusions about the central role cadherin-11, especially given the complex nature of the phenotype and the need to better contextualize these observations in a complete picture of metastasis.
We extend our gratitude to eLife for affording us the opportunity to publish our manuscript as a peer-reviewed preprint. We acknowledge that our exploration of the novel cell hijacking mechanism underlying cancer metastasis …
Author Response
eLife assessment
This paper presents a series of experiments investigating the role of cadherin-11 mediated interactions between cancer cells and fibroblasts in metastasis using updated 3D cell co-invasion assays. The primarily descriptive data are a valuable contribution to our understanding of the nature of cross cell-type interactions in metastasis, but are incomplete with respect to the far-reaching conclusions about the central role cadherin-11, especially given the complex nature of the phenotype and the need to better contextualize these observations in a complete picture of metastasis.
We extend our gratitude to eLife for affording us the opportunity to publish our manuscript as a peer-reviewed preprint. We acknowledge that our exploration of the novel cell hijacking mechanism underlying cancer metastasis remains an evolving endeavor. Being the inaugural study to introduce this innovative phenotype, substantiated by comprehensive in vivo investigations that underscore its real-world significance, we eagerly anticipate forthcoming research in this domain. The inception of the concept of cancer metastasis dates back to the 18th century. Throughout the extensive journey marked by a multitude of millions of publications in this field, our work introduces a transformative and disruptive dimension with the unveiling of this cell hijacking mechanism. Simultaneously, it initiates a deeper exploration of the intricacies within the metastatic process. We sincerely value the meticulous assessment of our work and look forward to subsequent investigations that will elucidate these findings within the broader context of metastasis.
Joint Public Review:
The authors of this manuscript studied cell-cell interaction between fibroblast and cancer cells as an intermediary model of tumor cell migration/invasion. The work focused on the mesenchymal cadherin-11 (CDH11) which is expressed in the later stages of the epithelial mesenchymal transition (EMT) in tumor cellular models, and whose expression is correlated with tumor progression in vivo. The authors employed 3-D matrix and live cell imaging to visualize the nutrient-dependent co-migration of fibroblast and cancer cells. By siRNA-based suppression of CDH11 expression in tumor cell line and/or fibroblast cells, the authors observed decreased co-movement and attenuated growth of mixed xenograft. Accordingly, the authors conclude that post-EMT cancer cells are capable of migrating/invading through CDH11-mediated cell-cell contact.
While the data point to the involvement of CDH11 in fibroblast mediated co-invasion, as it stands it is difficult to fully contextualize these observations within the broader context of the molecular mechanisms underlying metastasis, and in particular do not firmly establish a primary role for CDH11 at this time. The reviewers were specifically concerned about indirect effects of CDH11 manipulation on the physiology and cell biology of the tumor cells, and the possibility that several of the results could be consequences of these changes rather than due specifically to CDH11 mediated interactions.
The reviewers acknowledge the difficulty in fully controlling for these phenomena, and believe this work will be of interest to the large number of researchers investigating the molecular basis for metastasis and specifically of trans cell-type interactions. However until experiments establishing the specific formation and CDH11-mediated interactions in co-invasion are carried out, the author's conclusions about the prominent role of CDH11 should be treated as intriguing, but speculative.
We extend our sincere gratitude to the peer reviewers for their invaluable and constructive feedback. We also wish to express our appreciation for the concise summary of our study and the recognition of the challenges posed by the current technological landscape in fully elucidating the phenotype.
In response to the reviewer's concerns regarding the indirect effects of CDH11 manipulation on the physiology and cellular biology of tumor cells, we encourage readers to revisit Figure 3. In this figure, we not only silenced CDH11 in cancer cells but also in fibroblasts. The outcomes of this intricate experiment have been comprehensively discussed in the main text and are visually summarized in Supplemental Figure S2.
Furthermore, we draw attention to a comprehensive review of our in vivo studies presented in Figure 6, wherein we exclusively silenced CDH11 in fibroblasts without any manipulation of the cancer cells. These findings underscore the molecular underpinnings of CDH11 as the mediator of cell hijacking. Consequently, we are confident that the reviewer's concerns regarding potential side effects of CDH11 manipulation on tumor cells, which could weaken the manuscript's conclusions, can be addressed.
In conclusion, we wish to emphasize that we shared the same initial concerns as our reviewers when designing these studies. We have diligently endeavored to alleviate these concerns through a series of comprehensive in vitro, ex vivo, and in vivo experiments. Once again, we strongly encourage readers to explore our supplemental data for a more in-depth understanding. Thank you.
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eLife assessment
This paper presents a series of experiments investigating the role of cadherin-11 mediated interactions between cancer cells and fibroblasts in metastasis using updated 3D cell co-invasion assays. The primarily descriptive data are a valuable contribution to our understanding of the nature of cross cell-type interactions in metastasis, but are incomplete with respect to the far-reaching conclusions about the central role cadherin-11, especially given the complex nature of the phenotype and the need to better contextualize these observations in a complete picture of metastasis.
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Joint Public Review:
The authors of this manuscript studied cell-cell interaction between fibroblast and cancer cells as an intermediary model of tumor cell migration/invasion. The work focused on the mesenchymal cadherin-11 (CDH11) which is expressed in the later stages of the epithelial mesenchymal transition (EMT) in tumor cellular models, and whose expression is correlated with tumor progression in vivo. The authors employed 3-D matrix and live cell imaging to visualize the nutrient-dependent co-migration of fibroblast and cancer cells. By siRNA-based suppression of CDH11 expression in tumor cell line and/or fibroblast cells, the authors observed decreased co-movement and attenuated growth of mixed xenograft. Accordingly, the authors conclude that post-EMT cancer cells are capable of migrating/invading through CDH11-mediated …
Joint Public Review:
The authors of this manuscript studied cell-cell interaction between fibroblast and cancer cells as an intermediary model of tumor cell migration/invasion. The work focused on the mesenchymal cadherin-11 (CDH11) which is expressed in the later stages of the epithelial mesenchymal transition (EMT) in tumor cellular models, and whose expression is correlated with tumor progression in vivo. The authors employed 3-D matrix and live cell imaging to visualize the nutrient-dependent co-migration of fibroblast and cancer cells. By siRNA-based suppression of CDH11 expression in tumor cell line and/or fibroblast cells, the authors observed decreased co-movement and attenuated growth of mixed xenograft. Accordingly, the authors conclude that post-EMT cancer cells are capable of migrating/invading through CDH11-mediated cell-cell contact.
While the data point to the involvement of CDH11 in fibroblast mediated co-invasion, as it stands it is difficult to fully contextualize these observations within the broader context of the molecular mechanisms underlying metastasis, and in particular do not firmly establish a primary role for CDH11 at this time. The reviewers were specifically concerned about indirect effects of CDH11 manipulation on the physiology and cell biology of the tumor cells, and the possibility that several of the results could be consequences of these changes rather than due specifically to CDH11 mediated interactions.
The reviewers acknowledge the difficulty in fully controlling for these phenomena, and believe this work will be of interest to the large number of researchers investigating the molecular basis for metastasis and specifically of trans cell-type interactions. However until experiments establishing the specific formation and CDH11-mediated interactions in co-invasion are carried out, the author's conclusions about the prominent role of CDH11 should be treated as intriguing, but speculative.
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