Modeling Tumor Invasion with Spheroids Embedded in Extracellular Matrix

在过去的十年里，许多实验工作都集中在肿瘤周围组织的硬化和纤维排列如何将肿瘤转变为更具侵袭性和侵袭性的表型。在理论方面，最近在模拟光纤网络中的应变-硬化转变以及模拟单细胞在光纤网络中的迁移方面取得了进展。然而，基于细胞的模型尚未描述大量细胞集合如何与周围组织相互作用，因此无法预测观察结果，例如共同离开肿瘤的细胞流。这一令人惊讶的理论差距的一个可能原因是，模拟细胞-细胞外基质相互作用需要一个框架，同时描述细胞化和无细胞化的组织以及它们之间的(可能是错综复杂的)界面，以及最少的直接可观察的参数，如细胞形状和纤维网络微结构。新的实验技术将允许PI执行测量，这些测量不仅可以针对建模进行直接测试，而且还将帮助指导建模。在癌症等癌症的临床治疗中，很难识别出正确预测单个患者肿瘤侵袭性的生物标志物。也很难量化肿瘤的微环境如何改变特定患者的预后。这里提出的研究将使用与癌症生物学实验室通常探索的想法相辅相成的想法来解决这两个问题，确定可通过实验获得的指标如何与肿瘤侵袭性甚至患者预后相关。PI表明，结构生物标记物，如细胞形状和纤维排列，可能共同作用来确定肿瘤的侵袭性。为了扩大对组织力学和活性物质日益增长的跨学科领域的参与，国际物理学会将建立一个跨部门和跨大学的软物质-生物学期刊俱乐部，并将设计一个关于“癌症的软物质物理学”的短期课程，在博尔德凝聚态物质学院和其他暑期学校等场所传播。这些努力应该有助于引起新一代人对软物质和生物学交叉的重要问题的兴趣。PI将使用理论和实验工具来量化多细胞肿瘤球体与其细胞外基质(ECM)环境之间的相互作用。他们的假设是，整体流变学和界面能对球体和ECM如何相互作用以稳定或破坏肿瘤边界的方式施加了强烈的限制，从而控制了肿瘤的侵袭性。他们之前的理论工作表明，密度高、细胞化的肿瘤的顶点模型和无细胞细胞外基质(ECM)的纤维网络模型都显示出类似的刚性转变，推动了它们各自的流变性。其他的理论工作已经仔细地描述了这些模型中两种不同组织类型之间的界面令人惊讶的动态。最后，他们开发了一种强大的实验技术来探索单个乳腺肿瘤细胞和细胞外基质之间的机械相互作用。这项技术现在将应用于多细胞肿瘤球体。因此，在这个模型系统中，PI很好地开发了对肿瘤侵袭的可测试预测。他们将首先从理论和实验上研究肿瘤球体的流变学如何通过机械敏感的界面能调节细胞-细胞间和细胞-细胞间黏附之间的竞争，从而形成稳定的肿瘤-细胞外基质边界。然后，他们将研究在较长时间尺度上相关的细胞生长如何影响这种竞争，从而导致可变形和繁殖的、稳定的肿瘤-ECM边界。最后，他们将探索在什么条件下，椭圆形-ECM边界最终在个人和/或多细胞尺度上不稳定，导致对周围组织的入侵。这一裁决反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Over the past decade, much experimental work has focused on how stiffening and fiber alignment in the tissue around a tumor can transform the carcinoma into a more aggressive and invasive phenotype. On the theory side, there has been recent progress on modeling strain-stiffening transitions in fiber networks, as well as modeling single-cell migration through fiber networks. However, cellular-based models have yet to describe how large collections of cells interact with surrounding tissue, and therefore cannot predict observations such as cellular streams that leave a tumor collectively, for instance. One possible reason for this surprising theoretical gap is that modeling cell-ECM interactions requires a framework that simultaneously describes cellularized and acellularized tissues as well as a (possibly convoluted) interface between them, with a minimal number of directly observable parameters, such as cell shape and fiber network microarchitecture. New experimental techniques will allow the PIs to perform measurements that can not only be directly tested against the modeling but will help guide the modeling as well. In the clinical treatment of cancers like carcinomas, it is difficult to identify biomarkers that correctly predict the aggressiveness of a tumor in an individual patient. It is also difficult to quantify how the microenvironment of a tumor might alter the prognosis for a particular patient. The research proposed here will address these two problems using ideas that are complementary to the ones typically being explored in cancer biology labs, by identifying how experimentally-accessible metrics correlate with tumor invasiveness and perhaps even patient outcomes. The PIs suggest that structural biomarkers such as cell shape and fiber alignment may work together to specify tumor invasiveness. To broaden the participation in the growing interdisciplinary fields of tissue mechanics and active matter, the PIs will establish an inter-departmental and inter-university soft matter-biology journal club and will devise a short course on “the soft matter physics of cancer” to disseminate at venues such as the Boulder school for condensed matter and other summer schools. These endeavors should help generate interest among a new generation in important problems at the intersection of soft matter and biology.The PIs will use theoretical and experimental tools to quantify the interactions between a multicellular tumor spheroid and its extracellular matrix (ECM) environment. Their hypothesis is that bulk rheology and interfacial energies place strong constraints on how the spheroid and ECM interact to stabilize or destabilize the tumor boundary and, thereby, govern tumor invasiveness. Their prior theoretical work demonstrates that both vertex models for dense, cellularized tumors and fiber network models for the acellular extracellular matrix (ECM) exhibit similar rigidity transitions driving their respective rheologies. Additional theoretical work has carefully characterized the surprising dynamics of interfaces between two different tissue types in these models. Finally, they have developed a powerful experimental technique to probe the mechanical interactions between single breast tumor cells and extracellular matrices. This technique will now be applied to multicellular tumor spheroids. Therefore, the PIs are well-poised to develop testable predictions for tumor invasion in this model system. They first will theoretically and experimentally study how the rheology of the tumor spheroid, coupled to the ECM, via a mechanosensitive interfacial energy modulates the competition between cell-cell adhesion and cell- ECM adhesion to deform a stable tumor-ECM boundary. They will then investigate how cell growth, relevant at longer time scales, affects this competition to lead to deformable and propagating, stable tumor-ECM boundaries. Finally, they will explore under what conditions the spheroid-ECM boundary ultimately destabilizes at the individual and/or multicellular scale to lead to invasion of the surrounding tissue.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.