CAREER: Force-Generating Mechanisms Responsible for Matrix-Dependent Compressive Mechanical Feedback During Tumor Growth

生长是身体器官和结构发育的必要过程。这是一个复杂的过程，涉及细胞内、细胞之间以及细胞与其周围基质之间的信号。在生长过程中，细胞分裂--导致器官或结构膨胀，推动周围的基质。基质起到约束分裂细胞的作用。这种对基质的膨胀导致在细胞上产生压缩力。目前还不清楚这种约束诱导的压缩如何影响未来的细胞分裂和生长。然而，众所周知，像癌症这样的疾病会导致肿瘤表面上的混乱生长，通常会在比健康基质坚硬得多的基质中启动和蓬勃发展。这个学院早期职业发展计划(CALEAR)奖励项目将寻求确定细胞如何决定约束诱导的压力对它们的生长是健康的，以及肿瘤细胞如何逃避这些信号。这一奖项有望带来的知识进步随后可用于支持癌症新治疗和表征系统的开发。该项目还将吸引、激励和教育未来的科学家和社区，让他们了解机械在健康和疾病中的重要性。这些教育和推广活动包括面向年轻高中生的三个互动模块，参加高中生住宿研究暑期项目，指导本科生研究人员，开发研究生水平的课程，甚至与舞蹈演员合作，向广大观众传播生物力学的概念。该项目的总体研究目标是研究恶性组织中的组织生长作为细胞外基质的机械特性的函数，重点在于了解细胞在组织生长过程中传递机械约束的信号通路和细胞骨架网络力学。这是通过三个研究目标来支持的。第一个目标将确定乳腺癌细胞的增殖潜力和细胞和组织规模的形态发展，在使用明确定义的水凝胶基质的机械约束生长过程中，乳腺癌细胞的侵袭性增加。与细胞和组织形态以及细胞分裂相关的测量将使用时间推移共聚焦显微镜作为存在的细胞数量和基质机械性能的函数来量化。第二个目标将比较基质和组织中的组织和细胞尺度的应力场，以增加侵袭性的乳腺癌细胞组。这将通过使用与细胞共同嵌入基质中的荧光微珠对生长过程中造成的组织变形进行成像来完成。最终的目标是通过检测细胞分裂过程中与力产生和感觉有关的蛋白质的表达，并部分抑制这些蛋白质来辨别它们各自的作用，以确定细胞在分裂过程中传递机械约束的机制。这项工作的科学影响将是重大的，因为它将显著有助于从根本上理解肿瘤的生长和发展--必须回答的关键问题，才能使癌症治疗的未来发展。这一奖项反映了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。

Growth is a necessary process to develop the organs and structures of the body. It is a complex process involving signals inside cells, between cells, and between cells and their surrounding matrix. During growth, cells divide -- leading to expansion of the organ or structure that pushes against the matrix that surrounds it. The matrix acts to constrain the dividing cells. This expansion against the matrix results in a compressive force being generated on the cells. It is not currently understood how this constraint-induced compression affects future cell division and growth. However, it is known that diseases like cancer, which lead to the seemingly chaotic growth of tumors, often initiate and flourish in matrices that are significantly stiffer than healthy matrices. This Faculty Early Career Development Program (CAREER) award project will seek to determine how cells decide how much constraint-induced compression is healthy for them to grow against and how tumor cells evade such signals. The advancement in knowledge expected from this award can then be applied to support development of new treatment and characterization systems for cancer. The project will also engage, motivate, and educate future scientists and the community on the importance of mechanics in health and disease. These educational and outreach activities include three interactive modules for young high school students, participating in residential research summer programs for high school students, mentoring undergraduate student researchers, developing a graduate-level curriculum, and even collaborating with dancers to develop performances that communicate concepts of biomechanics to a broad audience.The overall research goal of this project is to study tissue growth in malignant tissue as a function of the mechanical properties of the extracellular matrix, focusing on understanding the signaling pathways and cytoskeletal network mechanics through which cells transduce mechanical constraint during tissue growth. This is supported through three research objectives. The first objective will determine the proliferative potential and cell- and tissue-scale morphological development of breast cancer cells of increasing aggressiveness during mechanically constrained growth using well-defined hydrogel matrices. Measurements related to cellular and tissue morphology, as well as cellular division, will be quantified using time-lapse confocal microscopy as a function of the number of cells present and the matrix mechanical properties. The second objective will compare tissue- and cell-scale stress fields in the matrix and tissue for the panel of breast cancer cells of increasing aggressiveness. This will be done through imaging of tissue deformation caused during growth using fluorescent microbeads co-embedded in the matrix with the cells. The final objective seeks to determine the mechanism by which cells transduce mechanical constraint during division in tissue growth by examining the expression of proteins that are involved with force generation and sensing during cellular division and partially inhibiting those proteins to discern their individual roles. The scientific impact of this work will be significant, as it will significantly contribute to the fundamental understanding of tumor growth and development -- key questions that must be answered to allow future developments in cancer treatment.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.