Investigating the Biophysics of Giant Polyploidal Cancer Cells in an Aging Tumor Stroma

一般认为，衰老或细胞老化和死亡对肿瘤生长是一件好事，因为正在恶化和死亡的细胞不会继续生长和增殖。然而，已经发现，如果衰老的结缔组织细胞（基质细胞）在癌前组织中积累，它们实际上可以改变组织微环境并促进癌症发展。该项目将研究乳腺癌细胞如何对细胞外机械环境的变化做出反应，这种变化是随着衰老基质细胞的积累而发生的。特别是，巨大的多倍体癌细胞，已被观察到在衰老的基质细胞的存在下更频繁地发展，并且具有高度侵袭性和对化疗的抗性，将被研究以确定这种环境变化如何影响它们的发展。除了提高对这些侵入性，耐药细胞如何发展的理解将产生的影响外，研究小组还将组织外展活动，包括在当地学校进行演讲，为布朗科学预备课程开发课程材料，以及开发动画，科学-基于卡通的描述癌症生物力学。这个项目将研究乳腺癌细胞的单细胞生物物理特征，在暴露于来自衰老基质细胞的条件培养基后。特别是，高含量的力学筛选方法将用于分析：细胞对细胞外基质施加的力;细胞骨架和核力学;形态学，运动性和粘附性。这将用于治疗和未治疗的乳腺癌细胞以及巨大的多倍体癌细胞。通过观察细胞内力学、细胞和核形态、牵引力产生和运动性的变化，有可能开发出靶向巨大多倍体癌细胞的新策略。此外，由于假设来自周围组织的固体应力有助于在巨大的多倍体癌细胞中看到的有丝分裂出芽，因此将开发一个模型来验证这一假设。该奖项反映了NSF的法定使命，并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，被认为值得支持。

Generally it is assumed that senescence, or cell aging and death, is a good thing when it comes to tumor growth -- as cells that are deteriorating and die will not continue to grow and proliferate. However, it has been found that if senescent connective tissue cells (stromal cells) accumulate in premalignant tissue, they can actually alter the tissue microenvironment and promote cancer development. This project will investigate how breast cancer cells react to the changes in the extracellular mechanical environment that occurs with the accumulation of senescent stromal cells. In particular, giant polyploidal cancer cells, which have been observed to develop more frequently in the presence of senescent stromal cells and are highly invasive and resistant to chemo therapy, will be studied to determine how this environmental change influences their development. In addition to the impact that improved understanding of how these invasive, treatment-resistant cells develop will have, the research team will organize outreach activities that include presentations at local schools, development of course materials for the Brown Science Prep program, and the development of an animated, science-based cartoon that describes cancer biomechanics.This project will investigate the single cell biophysical profile of breast cancer cells before and after exposure to conditioned media from senescent stromal cells. In particular, a high-content mechanomic screening approach will be used to profile: the forces exerted by cells on the extracellular matrix; cytoskeletal and nuclear mechanics; morphology, motility, and adhesion. This will be done for treated and untreated breast cancer cells as well as giant polyploidal cancer cells. By looking at changes in intracellular mechanics, cell and nuclear morphology, traction force generation, and motility, it may be possible to develop new strategies to target giant polyploidal cancer cells. In addition, as it is hypothesized that solid stress from the surrounding tissue contributes to a-mitotic budding seen in giant polyploidal cancer cells, a model will be developed to test the hypothesis.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.