Diversity in cancer invasion phenotypes indicates specific stroma regulated programs
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RESEARCH ARTICLE
Diversity in cancer invasion phenotypes indicates specific stroma regulated programs Ashkan Novin1,2 · Yasir Suhail1,2,3 · Visar Ajeti1,3 · Ruchi Goyal1 · Khadija Wali1,4 · Atta Seck1,5 · Alex Jackson1 · Kshitiz1,3,6 Received: 3 July 2020 / Accepted: 3 September 2020 © Japan Human Cell Society 2020
Abstract Tumor dissemination into the surrounding stroma is the initial step in a metastatic cascade. Invasion into stroma is a nonautonomous 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. Keywords Stromal invasion · Collective invasion · Cancer-stroma interaction
Introduction
Yasir Suhail, Visar Ajeti, Ruchi Goyal, Khadija Wali, Atta Seck contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13577-020-00427-6) contains supplementary material, which is available to authorized users. * Kshitiz [email protected] 1
Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, USA
2
Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA
3
Cancer Systems Biology@ Yale, New
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