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、细胞间以及细胞与周围基质之间的信号。在生长过程中，细胞分裂--导致器官或结构的扩张，从而推动周围的基质。基质的作用是限制分裂的细胞。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，导致肿瘤看似混乱的生长，通常在比健康基质明显更硬的基质中开始和蓬勃发展。这个教师早期职业发展计划（CAREER）奖项目将寻求确定细胞如何决定多少约束诱导的压缩是健康的，他们反对生长，以及肿瘤细胞如何逃避这些信号。该奖项预期的知识进步可以应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对健康和疾病的力学的重要性。这些教育和推广活动包括三个互动模块，为年轻的高中生，参加住宅研究夏季计划的高中生，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，开发向广大观众传达生物力学概念的表演。该项目的总体研究目标是研究恶性肿瘤中的组织生长，组织作为细胞外基质的机械性能的函数，侧重于理解信号通路和细胞骨架网络力学，细胞通过这些机制在组织生长过程中克服机械约束。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，增加侵略性，在机械约束的生长过程中，使用定义明确的水凝胶基质。与细胞和组织形态以及细胞分裂相关的测量将使用延时共聚焦显微镜作为存在的细胞数量和基质机械性质的函数进行定量。第二个目标将比较组织和细胞规模的应力场的矩阵和组织的面板乳腺癌细胞的侵略性增加。这将通过使用与细胞共嵌入基质中的荧光微珠对生长期间引起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知有关的蛋白质的表达，并部分抑制这些蛋白质以辨别其各自的作用，来确定细胞在组织生长分裂过程中克服机械约束的机制。这项工作的科学影响将是显著的，因为它将大大有助于对肿瘤生长和发展的基本理解--这是癌症治疗未来发展必须回答的关键问题。该奖项反映了NSF的法定使命，并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，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.