Modeling Tumor Invasion with Spheroids Embedded in Extracellular Matrix

在过去的十年中，许多实验工作都集中在肿瘤周围组织中的硬化和纤维排列如何将癌转化为更具侵袭性和侵袭性的表型。在理论方面，最近在模拟纤维网络中的应变硬化转变以及模拟通过纤维网络的单细胞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如何与周围组织相互作用，因此无法预测观察结果，例如集体离开肿瘤的细胞流。这种令人惊讶的理论差距的一个可能原因是，建模细胞-ECM相互作用需要一个框架，该框架同时描述细胞化和去细胞化组织以及它们之间的（可能是复杂的）界面，具有最少数量的直接可观察的参数，例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，不仅可以直接针对建模进行测试，而且还有助于指导建模。在癌症如癌的临床治疗中，难以鉴定正确预测个体患者中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互补的想法来解决这两个问题，通过确定实验可获得的指标如何与肿瘤侵袭性甚至患者结果相关。PI表明，结构生物标志物，如细胞形状和纤维排列可能共同作用，以指定肿瘤的侵袭性。为了扩大对组织力学和活性物质等日益增长的跨学科领域的参与，PI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，在博尔德凝聚态学校和其他暑期学校等场所进行宣传。这些努力应该有助于新一代人对软物质和生物学交叉点的重要问题产生兴趣。PI将使用理论和实验工具来量化多细胞肿瘤球体及其细胞外基质（ECM）环境之间的相互作用。他们的假设是，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并从而控制肿瘤侵袭力施加了强约束。他们先前的理论工作表明，致密的细胞化肿瘤的顶点模型和无细胞细胞外基质（ECM）的纤维网络模型都表现出类似的刚性转变，从而驱动其各自的流变学。额外的理论工作已经仔细地表征了这些模型中两种不同组织类型之间界面的令人惊讶的动力学。最后，他们开发了一种强大的实验技术来探测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，PI已准备好在该模型系统中开发可测试的肿瘤侵袭预测。他们首先将从理论上和实验上研究肿瘤球体的流变学如何与ECM偶联，通过机械敏感的界面能调节细胞-细胞粘附和细胞- ECM粘附之间的竞争，以使稳定的肿瘤-ECM边界变形。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肿瘤-ECM边界。最后，他们将探索在什么条件下，球体ECM边界最终在个人和/或多细胞规模不稳定，导致周围组织的入侵。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.