Physical Models for Cancer Cells with Links to Alterations in Genome Organization

癌症是一种由连续体细胞突变的稳定积累引起的进化性疾病。通过获得适应性优势，癌细胞经历快速生长。 该奖项的总体目标是利用理论和计算为癌症和正常细胞混合物的集体运动提供定量预测，并将其与基因组组织和动力学的变化联系起来。为了实现这些目标，主要研究者（PI）将创建物理模型，以阐明两种细胞类型混合物中集体细胞动力学的原理。PI还将研究正常细胞和癌细胞之间染色体三维组织和动力学的差异。PI希望使用基于物理学的思想解决的两个主要问题来自以下观察。首先，目前尚不清楚单个癌细胞的产生如何与正常细胞相互作用，并最终在不受控制的情况下扩散。第二，正常细胞和癌细胞在通过细胞阻塞引起的收缩时的运动有什么不同？所提出的问题是通过调查最近的实验产生的问题，可以用理论和计算方法定量解决。为了解决癌细胞如何侵入正常细胞的空间，在这个奖项中，研究人员将开发方法来解决癌细胞与正常细胞混合时的组织和动力学。事实上，在组织形成的所有方面，从癌症和其他疾病期间的结构发育到分解，描述多种细胞类型如何组织自己是一个困难但重要的问题。在这个奖项中，研究人员将开发新的模型来模拟细胞混合物的结构和动力学，作为细胞-细胞粘附，细胞-基质相互作用，细胞分裂和细胞凋亡的函数。第二个目标是研究正常细胞和癌细胞中通过染色体收缩的细胞运动的影响。当细胞移动时，它们的运动通过细胞堵塞而受到限制，由细胞的自我拥挤和限制驱动，这深刻地影响了染色质结构，可能导致基因表达的改变。最近的实验已经让我们看到了正常细胞和癌细胞之间染色体组织的差异。原发性肿瘤迁移到远处的能力涉及癌细胞侵入健康组织的级联步骤。在迁移过程中，癌细胞不得不，至少偶尔，挤压通过细胞周围的细胞外基质中的收缩。 收缩的大小可能小于细胞核的大小，这可能会使细胞中的基因组变形。 这个奖项需要回答的自然问题是：细胞核的变形是否改变了染色体的组织？通过使用理论方法来定量地理解这些实验，人们可以获得什么样的见解？解决这些问题需要开发大致从分子尺度到组织水平的模型。该奖项的更广泛影响将包括策划软件的开发，这些软件将公开提供。该奖项还将有助于培养跨学科领域的学生和博士后研究员。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估来支持。

Cancer is an evolutionary disease caused by steady accumulation of sequential somatic mutations. By gaining fitness advantage, cancer cells undergo rapid growth. The overarching goals of this award are to use theory and computations to provide quantitative predictions for collective motions of mixtures of cancer and normal cells and link them to changes in genome organization and dynamics. To accomplish the goals, the Principal Investigator (PI) will create physical models to elucidate the principles governing collective cell dynamics in mixtures of two cell types. The PI will also investigate the differences in the three-dimensional organization and dynamics of chromosomes between normal and cancer cells. The two major problems that the PI wishes to solve, using physics-based ideas, emerge from the following observations. First, it is unclear how the generation of a single cancer cell interacts with normal cells, and eventually spreads without control. Second, what are the differences between movements of normal and cancer cells as they move through constrictions that arise through cell jamming? The proposed problems were generated by surveying recent experiments have generated questions that can be quantitatively addressed using theoretical and computational methods. To address how cancer cells invade the space of normal cells, in this award, the investigators will develop methods to solve the organization and dynamics when cancer cells are mixed with normal cells. Indeed, in all aspects of tissue formation, ranging from development to breakdown of their structures during cancer and other diseases, the description of how multiple cell types organize themselves is a difficult but an important issue. In this award, the Investigators will develop novel models to simulate the structures and dynamics of mixtures of cells as a function of cell-cell adhesion, cell-matrix interactions, and cell division, and apoptosis. The second goal is to study the effect of cell movement through constrictions on chromosomes in normal and cancer cells. As cells move, their motions are constricted through cell jamming, driven by self-crowding of cells and confinement, which profoundly affect chromatin structures, possibly resulting in altered gene expression. Most recent experiments have given glimpses of the differences in the chromosome organization between normal and cancer cells. The ability of a primary tumor to migrate to distant parts involves a cascade of steps in the invasion of the cancer cells into heathy tissues. During migration, cancer cells have to, at least occasionally, squeeze through constrictions in the extra cellular matrix surrounding the cells. The sizes of the constrictions could be smaller than the nucleus size, which potentially deforms the genome in the cells. The natural questions that need to be answered by this award are: Does the deformation of the nucleus alter the organization of the chromosomes? What insights can one gain by using theoretical methods to quantitatively understand these experiments? Answering these questions requires development of models that go roughly from the molecular scale to tissue level. The broader impacts of this award will include the development of curated software, which will be made publicly available. This award will also contribute to the training of students and postdoctoral fellows in interdisciplinary fields.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.