Solid stress, one of the physical hallmarks of cancer, is defined as the mechanical force generated and transmitted by the solid components of a tumor. Solid stress affects the trafficking and infiltration of immune cells, promotes metastasis and tumorigenic pathways, and impedes therapeutic delivery. Despite these clinical ramifications, questions remain regarding the origins and consequences of solid stresses. Answering these fundamental questions requires probing solid stresses at the cellular scale, where biological and immunological responses manifest, as well as in vivo, where the complexities of the tumor microenvironment exist.
Here, we present the first in vivo, multi-scale optical measurements of solid stress in tumors using intravital imaging of deformable polyacrylamide hydrogel spheres embedded within primary tumors or in lung metastatic tumors through the hematogenous route. Our approach leverages multimodal intravital microscopy to obtain 3-D high-resolution spatial and longitudinal measurements of solid stresses in vivo. We measure and compare solid stresses (i) in primary vs metastatic tumors, (ii) in vivo vs in vitro settings, and (iii) at the single cell vs tissue scale. We compared the solid stresses in primary breast tumors vs breast cancer lung metastasis. We found that solid stresses are significantly higher in metastatic settings, although both metastatic and primary tumors were induced from the same cancer cells. Our results demonstrate the role of the microenvironment on solid stress genesis and potential implications on the differential treatment response between primary and metastatic settings. Furthermore, our method enables the comparison between the in vitro and in vivo models of solid stresses to evaluate how closely these in vitro models recapitulate the physical tumor microenvironment. While it has been shown through mathematical modeling that stress transmission is scale-dependent, we reveal for the first time experimentally that solid stress transmission is scale-dependent. Interestingly, we find that the stresses that individual tumor cells experience are a factor of 5–8 lower than the large stress levels measured at the tissue scales. This finding lays the groundwork for discovering novel biophysical mechanisms that cancer cells utilize to evade cell death from high mechanical stresses, and for establishing new therapeutic strategies aimed at increasing the vulnerability of cancer cells to mechanical stresses, resulting in cancer cell death.
Furthermore, the dissertation delves into dispersion indices as a universal tool for quantifying biological images. Inspired by their use in measuring income distribution within human populations, dispersion indices are applied to the novel application of analyzing the distribution patterns of subcellular structures. This approach offers distinct advantages over traditional image analysis methods, especially in its ability to transcend the constraints imposed by developing separate tools for different biological systems. Dispersion indices are demonstrated to be effective in quantifying autophagic puncta, mitochondrial clustering, and microtubule dynamics. / 2026-05-23T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/48865 |
| Date | 24 May 2024 |
| Creators | Zhang, Sue Shuyi |
| Contributors | Nia, Hadi T., Grinstaff, Mark W. |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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