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Diversity in cancer invasion phenotypes indicates specific stroma regulated programs

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Abstract

Tumor dissemination into the surrounding stroma is the initial step in a metastatic cascade. Invasion into stroma is a non-autonomous process for cancer, and its progression depends upon the stage of cancer, as well as the cells residing in the stroma. However, a systems framework to understand how stromal fibroblasts resist, collude, or aid cancer invasion has been lacking, limiting our understanding of the role of stromal biology in cancer metastasis. We and others have shown that gene perturbation in stromal fibroblasts can modulate cancer invasion into the stroma, highlighting the active role stroma plays in regulating its own invasion. However, cancer invasion into stroma is a complex higher-order process and consists of various sub-phenotypes that together can result in an invasion. Stromal invasion exhibits a diversity of modalities in vivo. It is not well understood if these diverse modalities are correlated, or they emanate from distinct mechanisms and if stromal biology could regulate these characteristics. These characteristics include the extent of invasion, formation, and persistence of invasive forks by cancer as opposed to a collective frontal invasion, the persistence of invading velocity by leader cells at the tip of invasive forks, etc. We posit that quantifying distinct aspects of collective invasion can provide useful suggestions about the plausible mechanisms regulating these processes, including whether the process is regulated by mechanics or by intercellular communication between stromal cells and cancer. Here, we have identified the sub-characteristics of invasion, which might be indicative of broader mechanisms regulating these processes, developed methods to quantify these metrics, and demonstrated that perturbation of stromal genes can modulate distinct aspects of collective invasion. Our results highlight that the genetic state of stromal fibroblasts can regulate complex phenomena involved in cancer dissemination and suggest that collective cancer invasion into stroma is an outcome of the complex interplay between cancer and stromal fibroblasts.

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Funding

This research was funded by the UConn Health Startup fund provided by the UConn Health Dental School and Biomedical Engineering Department, as well as by National Cancer Institute, USA funded U54 sub-contract to UConn Health: 1U54CA209992-02.

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Author notes

  1. Yasir Suhail, Visar Ajeti, Ruchi Goyal, Khadija Wali, Atta Seck contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, USA

    Ashkan Novin, Yasir Suhail, Visar Ajeti, Ruchi Goyal, Khadija Wali, Atta Seck, Alex Jackson &  Kshitiz

  2. Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA

    Ashkan Novin & Yasir Suhail

  3. Cancer Systems Biology@ Yale, New Haven, CT, USA

    Yasir Suhail, Visar Ajeti &  Kshitiz

  4. Department of Biology, Central Connecticut State University, New Britain, CT, USA

    Khadija Wali

  5. College of Engineering, Technology, and Architecture, University of Hartford, Hartford, CT, USA

    Atta Seck

  6. Center for Cell Analysis and Modeling, University of Connecticut Health, Farmington, CT, USA

    Kshitiz

Authors
  1. Ashkan Novin
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  2. Yasir Suhail
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  3. Visar Ajeti
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  4. Ruchi Goyal
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  5. Khadija Wali
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  6. Atta Seck
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  7. Alex Jackson
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  8. Kshitiz
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Contributions

Conceptualization, K., and Y.S.; methodology, A.N., Y.S., V.A., K.W., R.G., A.S., A.J., and K.; software, Y.S.; validation, A.N.; resources, K.; data curation, A.N.; writing-original draft preparation, K., Y.S., A.N.; writing-review and editing, K., Y.S., A.N.; project administration, V.A., Y.S., K.; funding acquisition, K.

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Correspondence to Kshitiz.

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Novin, A., Suhail, Y., Ajeti, V. et al. Diversity in cancer invasion phenotypes indicates specific stroma regulated programs. Human Cell 34, 111–121 (2021). https://doi.org/10.1007/s13577-020-00427-6

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  • DOI: https://doi.org/10.1007/s13577-020-00427-6

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