Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor | Department of Biomedical Engineering | en_US |
| dc.contributor.advisor | Tan, Youhua (BME) | en_US |
| dc.creator | Zheng, Yufan | - |
| dc.identifier.uri | https://theses.lib.polyu.edu.hk/handle/200/13972 | - |
| dc.language | English | en_US |
| dc.publisher | Hong Kong Polytechnic University | en_US |
| dc.rights | All rights reserved | en_US |
| dc.title | Local niche softness-induced negative durotaxis promotes brain metastasis within the mechanically heterogeneous primary tumor | en_US |
| dcterms.abstract | Organotropism refers to the preferential but not random metastasis of tumor cells into specific organs, including brain. Brain metastasis is the most devastating cancer dissemination because of both the extremely poor patient survival and the perturbation of key neurological functions, such as cognition and sensation. Tumor microenvironment shapes metastatic organotropism, including brain tropism. Our previous study showed that long-term mechanical priming in soft niches in vitro shifted breast cancer organotropism to brain metastasis via the upregulation of histone deacetylase 3 (HDAC3) activity. However, it’s unclear whether and how the long-term soft-priming process is achieved in the mechanically heterogenous primary tumor to promote the brain metastasis. | en_US |
| dcterms.abstract | In this project, we developed a single-cell scale local niche softness biosensor, which enabled us to identify and separate tumor cells residing in local niches with different stiffnesses within tumor xenografts. With this biosensor, we found that local niche softness was not only correlated with the expressions of brain metastasis-related genes and HDAC3 activity, but also promoted the preferential metastasis of the resident cells into brain tissue. To unveil how soft niches impacted metastatic organotropism, we examined the influence of niche mechanics on cell mechanical behaviours, including durotaxis. Our results showed that soft-primed tumor cells and tumor cells isolated from local soft niches of xenografts were negative durotactic (i.e., migrating towards soft optimal microenvironment) and positive viscotactic (i.e., migrating towards microenvironment with high viscosity), both of which might ensure long-term residing of tumor cells in local soft niches of tumor xenografts. Importantly, soft niches promoted negative durotaxis via hyperactivation of integrin α10-Akt axis, which was required for niche softness-induced brain metastasis. Further, loss of brain metastatic potential abrogated negative durotaxis, indicating a reciprocal interaction between negative durotaxis and brain metastasis. We also uncovered a soft niche-specific cell competition that soft-primed tumor cells eliminated stiff-primed counterparts in an integrin α10-dependent manner. Besides, both soft-primed cells and niche softness inactivate cancer-associated fibroblasts locally, which maintained local niche softness. | en_US |
| dcterms.abstract | Collectively, we deciphered the crosstalk between local niche mechanics and tumor cells residing in the mechanically heterogenous primary tumor, elucidating that local soft niches enabled negative durotaxis of tumor cells to empower persistent priming and the acquisition of brain metastatic capability. | en_US |
| dcterms.extent | 1 volume (unpaged) : color illustrations | en_US |
| dcterms.isPartOf | PolyU Electronic Theses | en_US |
| dcterms.issued | 2025 | en_US |
| dcterms.educationalLevel | Ph.D. | en_US |
| dcterms.educationalLevel | All Doctorate | en_US |
| dcterms.accessRights | open access | en_US |
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