Epithelial layer jamming in breast cancer cell migration

 描述(申请人提供)：来自我们实验室的理论进展和实验证据现在证实，组成细胞在非恶性上皮细胞层内的迁移变得以与最近邻居的物理相互作用为主导，其方式与细胞干扰一致。随着细胞拥挤、细胞间黏附或协同细胞推进的改变，汇合的细胞集体可以经历从固体样堵塞阶段到流体样非堵塞阶段的转变，在该阶段中细胞容易交换位置和流动。临界标度指数理论预测，细胞粘附力的增加促进了类固体相向类流体非阻塞相的转变，并与细胞形状的变化有关。这一理论预测构成了我们的中心假设。重要的是，这一理论的预测与经典思维是矛盾的，但我们的初步数据证实了这一点。因此，这一细胞干扰理论带来了乳腺癌细胞迁移的新机制和新的物理图景。为了验证这一理论，在目标1中，我们将表征9个乳腺癌细胞系中选定的子集的干扰动力学，这些细胞系包括物理科学-肿瘤学网络的生物资源核心设施。在目标2中，我们将评估细胞-细胞黏附如何影响堵塞，特别关注在上皮向间充质转变(EMT)过程中细胞黏附的变化。在目标3中，我们将研究癌症干细胞的存在如何影响细胞干扰和集体运动。影响：癌症进展的关键一步是肿瘤细胞的集体迁移，但每个单独的细胞如何协调其迁移与邻近细胞的迁移，这违反了机械论的理解。在这里，我们提出了旨在揭示肿瘤进展早期集体细胞迁移的基本物理学的实验。从一整套实验探头获得的数据--细胞运动、牵引力、细胞间力1、2、4、7-9和细胞形状--将通过一种新的临界缩放理论的透镜进行批判性地看待。13，14这种细胞干扰理论是机械性的，不是微不足道的，而且是违反直觉的。如果得到我们的数据支持，这将不代表渐进的进步。相反，它可能会为癌症进展的物理学提供重要的新见解，而且因为它的预测是违反直觉和自相矛盾的，它可能会导致癌症治疗或预防的新策略。

 DESCRIPTION (provided by applicant): Theoretical advances and experimental evidence from our laboratories now establish that migration of the constituent cell within the non-malignant epithelial cellular layer becomes dominated by physical interactions with nearest neighbors in a manner that is consistent with cell jamming. With changes of cellular crowding, cell-cell adhesion, or cooperative cellular propulsion, the confluent cellular collective can undergo a transition from a solid-like jammed phase in which cells become virtually frozen in place, to a fluid-like, unjammed phase in which cells readily exchange places and flow. The theory of critical scaling exponents predicts that the transition from solid-like jammed to fluid-lke unjammed phases is promoted by increased cell adhesive forces and linked to changes in cell shape. This theoretical prediction comprises our central hypothesis. Importantly, predictions from this theory are paradoxical to classical thinking but are borne out nevertheless by our preliminary data. Hence, this theory of cell jamming brings with it a new mechanism and a new physical picture of breast cancer cell migration. To test this theory, in Aim 1 we will characteriz jamming dynamics in a selected subset of the 9 breast cancer cell lines comprising the Bioresource Core Facility of the Physical Sciences-Oncology Network. In Aim 2 we will assess how cell-cell adhesion affects jamming with a specific focus on the changes in cellular adhesion that occur during the epithelial-to-mesenchymal transition (EMT). In Aim 3 we will investigate how the presence of cancer stem cells influence cellular jamming and collective motion. Impact: A key step in cancer progression is collective tumor cell migration, but how each individual cell coordinates its migration with that of immediate neighbors has defied mechanistic understanding. Here we propose experiments designed to unveil basic physics of collective cellular migration in early stages of tumor progression. Data derived from a comprehensive suite of experimental probes -cellular motions, traction forces, intercellular forces1,2,4,7-9 and cellular shapes- will be critically viewed through the lens of a novel theory of critical scaling.13,14 This theory of cell jamming is mechanistic, non-trivial, and counterintuitive. If supported by our data, it will not represent an incremental advance. Rather, it may provide important new insights concerning the physics of cancer progression, and, because its predictions are counterintuitive and paradoxical, it may lead to novel strategies for cancer treatment or prevention.