| Author: | Tang, Kai |
| Title: | The mechanics of local niches in the primary tumor regulate breast cancer brain metastasis |
| Advisors: | Tan, Youhua (BME) Yang, Mo (BME) |
| Degree: | Ph.D. |
| Year: | 2023 |
| Subject: | Breast -- Cancer Brain metastasis Metastasis Hong Kong Polytechnic University -- Dissertations |
| Department: | Department of Biomedical Engineering |
| Pages: | viii, 164 pages : color illustrations |
| Language: | English |
| Abstract: | Breast cancer cells disseminate to and colonize other organs not randomly, but rather have the preferred metastatic sites, including bone, liver, lung, and brain, which is defined as "organotropism". Brain metastasis considerably deteriorates patient survival compared to the metastasis in other organs and thus requires urgent attention. Previous studies have indicated that tumor cells with the ability to metastasize to specific organs may pre-exist in the primary tumor, suggesting the significance of the primary tumor microenvironment and/or specific sub-clones with unique mutations. Accumulating evidence has demonstrated the importance of mechanical cues in tumor metastasis. However, it remains poorly understood whether and how local niche mechanics in the primary tumor influence breast cancer brain metastasis. In this project, our study explored the effect of soft local niches in the primary tumor on breast cancer brain metastasis. We found that 1-month culture on soft matrices (soft niches-primed cells) remarkably increased the expressions of the genes related to brain but not bone metastasis, which was independent of ligand type and cell type. RNA-seq analysis showed that softness-primed cells exhibited molecular features of neuron, implying the promotive effect on brain metastasis. Soft niches-primed cells had enhanced the survival in circulation, cerebral endothelium adhesion and blood-brain barrier (BBB) transmigration in vitro. Further, these cells exhibited the mechanoadaptation to the soft matrix mimicking brain tissue and a high secretion level of Serpin B2 which might confer defense evasion ability to tumor cells to circumvent metastasis-suppressive effects in the brain. Moreover, soft niches-primed cells displayed unique biophysical properties and mechanical memory. In vivo animal experiments showed that the priming on soft matrices enhanced BBB transmigration and colonization ability of breast cancer cells in the brain. Importantly, soft niches-primed breast cancer cells exhibited the ability to preferentially metastasize to the brain in vivo. Mechanistically, the priming of single cell-derived progenies with low brain metastasis ability on soft matrices increased the expressions of brain metastasis-related genes expression, proliferation rate on brain-mimicking matrices, and BBB transmigration ability. Further, histone deacetylase (HDAC)-mediated chromatin condensation and remodeling were required in the softness-induced changes in brain metastasis gene expression. Among these HDACs, HDAC3 activity was highly upregulated in soft niches-primed cells, and necessary but not sufficient for the gain of brain metastatic phenotype. Brain metastasis formation was effectively antagonized in vivo by inhibiting HDAC3. Further, extended disruption of actin cytoskeleton increased HDAC3 activity and induced the acquisition of brain metastasis ability. In contrast, the increase of actin polymerization or contractility on soft matrices inhibited HDAC3 activity and prevented the up-regulation of brain metastasis ability. Taken together, these findings demonstrate that soft niches in the primary tumor promote breast cancer brain metastasis, which depends on mechanotransduction-mediated HDAC3 activity, highlighting the significance of local microenvironmental mechanics in organotropism. This study unveils the regulatory role of local niche mechanics of the primary tumor in brain metastasis and provides new evidence to illustrate the importance of mechanics in tumor metastasis. |
| Rights: | All rights reserved |
| Access: | open access |
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