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.

肿瘤向周围基质的扩散是转移级联反应的第一步。侵入基质是癌症的非自主过程，其进展取决于癌症的阶段以及存在于基质中的细胞。然而，缺乏了解基质成纤维细胞如何抵抗、共谋或帮助癌症侵袭的系统框架，限制了我们对基质生物学在癌症转移中作用的理解。我们和其他人已经表明，基质成纤维细胞中的基因扰动可以调节癌症对基质的侵袭，突出了基质在调节其自身侵袭中所起的积极作用。然而，癌症侵入基质是一个复杂的高阶过程，由各种亚表型组成，这些亚表型共同导致侵袭。基质入侵在体内表现出多种方式。目前尚不清楚这些不同的模式是否相关，或者它们来自不同的机制，以及基质生物学是否可以调节这些特征。这些特征包括癌症的侵袭程度、形成和持续存在的侵袭性叉，而不是集体正面入侵，侵袭性叉尖端的前导细胞入侵速度的持续性等。我们假设量化集体的不同方面入侵可以为调节这些过程的合理机制提供有用的建议，包括该过程是受力学调节还是受基质细胞与癌症之间的细胞间通讯调节。在这里，我们已经确定了入侵的子特征，这可能表明调节这些过程的更广泛的机制，开发了量化这些指标的方法，并证明了基质基因的扰动可以调节集体入侵的不同方面。我们的研究结果强调，基质成纤维细胞的遗传状态可以调节癌症传播中涉及的复杂现象，并表明癌症集体侵入基质是癌症和基质成纤维细胞之间复杂相互作用的结果。