Interplay of adherens junctions and matrix proteolysis determines the invasive pattern and growth of squamous cell carcinoma

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    eLife assessment

    This study addresses several gaps that are evident with regards to cancer cell invasion in tissue. The approaches taken by this group encompassing mathematical modeling and experimental procedures are for the most part rigorous. The study is deemed as of high potential impact.

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Cancers, such as squamous cell carcinoma, frequently invade as multicellular units. However, these invading units can be organised in a variety of ways, ranging from thin discontinuous strands to thick ‘pushing’ collectives. Here we employ an integrated experimental and computational approach to identify the factors that determine the mode of collective cancer cell invasion. We find that matrix proteolysis is linked to the formation of wide strands but has little effect on the maximum extent of invasion. Cell-cell junctions also favour wide strands, but our analysis also reveals a requirement for cell-cell junctions for efficient invasion in response to uniform directional cues. Unexpectedly, the ability to generate wide invasive strands is coupled to the ability to grow effectively when surrounded by extracellular matrix in three-dimensional assays. Combinatorial perturbation of both matrix proteolysis and cell-cell adhesion demonstrates that the most aggressive cancer behaviour, both in terms of invasion and growth, is achieved at high levels of cell-cell adhesion and high levels of proteolysis. Contrary to expectation, cells with canonical mesenchymal traits – no cell-cell junctions and high proteolysis – exhibit reduced growth and lymph node metastasis. Thus, we conclude that the ability of squamous cell carcinoma cells to invade effectively is also linked to their ability to generate space for proliferation in confined contexts. These data provide an explanation for the apparent advantage of retaining cell-cell junctions in squamous cell carcinomas.

Article activity feed

  1. eLife assessment

    This study addresses several gaps that are evident with regards to cancer cell invasion in tissue. The approaches taken by this group encompassing mathematical modeling and experimental procedures are for the most part rigorous. The study is deemed as of high potential impact.

  2. Reviewer #1 (Public Review):

    Observations made on histological patterns of SCC tumor invasion prompt the authors to investigate the seemingly broad distribution of invasion strategies employed by SCC tumor cells in tissue. Using computational modelling and testing the arising predictions in two experimental models of SCC invasion, the authors conclude matrix proteolysis and cell-cell junctions to play key roles in determining invasion strand width and cell adhesion strength to be a minor contributor.

    Strengths of the study:
    - The authors acknowledge the complexity of invasion patterns employed by SCC tumor cells in tissue and provide new insight into the underlying complex cellular processes.
    - The approach of combining computational simulations and testing their predictions experimentally with two models is powerful.

    Weaknesses of the study:
    - Cell proliferation (affected by proteolysis and cell-cell junctions) is indicated as a key contributor to the generation of broad strand invasion. However, proliferation is not investigated using the same experimental models used to investigate invasion and is not included as a parameter in the computational models.
    - The outcomes of their KO strategies on the cell-matrix and cell-cell adhesion are not fully demonstrated.

  3. Reviewer #2 (Public Review):

    Kato, Jenkins, et al. investigates cell-intrinsic and environmental determinants of diverse modes of collective cancer cell invasion in mucosal squamous cell carcinoma (muSCC). To explore this large parameter space, the authors develop a Cellular Potts model recapitulating two distinct in vitro muSCC - cancer-associated fibroblast (CAF) co-culture models: an organotypic platform containing an air/extracellular matrix (ECM) interface and a spheroid model mimicking dermal invasion and confinement by 3D ECM. Integrating between in silico predictions and quantitative assessment of the two experimental platforms, the authors make several interesting observations regarding determinants of the mode of collective SCC invasion. Of these, the most significant include the ability of SCCs to invade with deletion of β1 integrin in their organotypic model although invasion phenotype is altered, and identification of a synergistic dependence on cell-cell adhesion and matrix proteolysis for controlling strand width and growth within the invading cohort. Cell-cell adhesions are essential for maintaining supracellular actomyosin coupling to coordinate the invading cohort, while matrix proteolysis is necessary for creating physical space that supports both invasion and cell growth within confined space.

    Overall, despite some concerns regarding support for specific claims, alternative considerations, and clarity in presentation, this study is rigorous and of high quality, and should serve as an important technical and conceptual resource that provides new insight into multicellular coordination in SCC invasion. More broadly, it illustrates the utility of coupling computational models with advanced 3D cell culture platforms to parse multifactorial control over complex forms of tissue morphogenesis.

  4. Reviewer #3 (Public Review):

    This study by Kato et. al used a combination of computational modeling, in vitro experimentation, and confirmatory in vivo mouse work to define what influences collective cell invasion in squamous cell carcinoma (SCC). Looking at a multitude of parameters, the authors found that cancer cell-cancer cell contacts and matrix degradation work cooperatively in SCC invasion.

    The authors provide a rigorous and systematic approach to querying the importance of the parameters tested; first setting their hypothesis computationally followed by in vitro experimentation in two different cancer cell culturing methods (organotypic and spheroid). Importantly, the experimental data convincingly confirmed the computational predictions, lending credence to their methodology. This is a major strength of the manuscript and will be beneficial to the field with regard to investigating invasion in other cancer types.

    Additionally, the varied parameters tested (cancer cell-cell adhesion, cancer cell-matrix adhesion, cancer cell-fibroblast adhesion, fibroblast-matrix adhesion, cell-intrinsic motility, matrix displacement, and matrix proteolysis) were thoughtful and rooted in the literature. However, though considerate of the role the extracellular matrix (ECM) may play (via interrogating cancer cell-matrix adhesions as parameters), the characteristics of the matrix itself (e.g. stiffness, alignment) were not investigated. These attributes have been previously shown to affect collective cell invasion. Indeed, while investigating the contributions of matrix proteolysis on invasion, the authors found a parabolic relationship where both too much and too little matrix negatively impacted the ability of SCC cells to invade. Moreover, it is unclear what the role of fibroblast-matrix adhesions was to this system, though it was originally stated as a tested parameter.