| Author: | Hu, Guanshuo |
| Title: | Local niche mechanics within primary tumors regulate breast cancer metastatic organotropism through metabolic reprogramming |
| Advisors: | Tan, Youhua (BME) |
| Degree: | Ph.D. |
| Year: | 2025 |
| Department: | Department of Biomedical Engineering |
| Pages: | x, 130 pages : color illustrations |
| Language: | English |
| Abstract: | Tumor cell dissemination from a primary lesion to distal organs is not random but exhibits organ preference, which is referred to as metastasis organotropism. Primary tumors as a whole have been found to be stiffer than healthy tissues and the significance of the altered mechanical microenvironment in malignancy has been increasingly appreciated. Nevertheless, heterogeneity is a hallmark of cancer, which could presumably lead to considerable variations in local niche stiffness within primary tumors. However, the roles of primary tumor mechanical heterogeneity in metastasis organotropism remain unclear. This study aimed to elucidate the relationship between primary tumor mechanical heterogeneity and metastasis organotropism. We found that soft niches in primary tumors promoted brain metastasis, while stiff niches facilitated bone metastasis. To validate the roles of local niche mechanics in vivo, we identified NDRG1 and ANKRD1 as candidate genes that were sensitive to niche softness and stiffness, respectively, and adopted them as niche mechanics biosensors. NDRG1-mCherry+ and ANKRD1-GFP+ cells isolated from the xenografts represented tumor cells residing in local soft and stiff niches and exhibited enhanced brain and bone metastatic potential. In order to faithfully replicate the complete steps of tumor metastasis, we developed an in vivo tracking cell system based on the NDRG1 and ANKRD1 promoters. Using this system, we discovered that cancer cells residing in soft and stiff regions of the primary tumor spontaneously metastasized to the brain and the bone, respectively. All these findings demonstrate that primary tumor mechanical heterogeneity regulates metastasis organotropism. Mechanistically, through single cell RNA-seq and bulk RNA-seq analysis, we discovered significant differences in metabolic profiles of soft- and stiff-primed tumor cells, which were further confirmed by LC-MS analysis. Specifically, tumor cells in soft niches exhibited a lipid metabolism pattern, while cells within stiff niches displayed an upregulation of glutamine metabolism. Using genetic and functional approaches, we demonstrated that soft niches enhanced lipid metabolism to promote brain metastasis, while stiff niches upregulated glutamine metabolism to facilitate bone metastasis. In order to elucidate how the niche mechanics-induced metabolic reprogramming influences metastatic organotropism, we conducted an integrated analysis of multiple datasets, revealing significant alterations in cellular metabolism, cytoskeletal rearrangement, and chromatin remodeling. Our data showed that in soft niches, lipid metabolism was associated with microtubule disruption and regulation of chromatin accessibility, while glutamine metabolism was linked to microtubule stabilization and modulation of chromatin accessibility in stiff niches. ATAC-seq analysis revealed that the genes associated with bone metastasis were in an open state within stiff niches, whereas the genes related to brain metastasis were in an open state within soft niches. Through integrated proteomics and transcription factor prediction, we discovered that BRG1 increased the accessibility of brain/bone metastasis-related genes by interacting with E2F1/JUND in soft/stiff niches. Furthermore, the binding of BRG1 with JUND in stiff niches was regulated by glutamine metabolism, while the binding of BRG1 with E2F1 in soft niches depended on lipid metabolism. Finally, through the analysis of single-cell sequencing samples from triple-negative breast cancer patients, we discovered that tumor cells residing in local soft niches exhibited a higher propensity for brain metastasis, while tumor cells in local stiff niches displayed a stronger capability for bone metastasis. Through the analysis of patient tissue biopsies, we discovered increased lipid metabolism in soft niches and elevated glutamine metabolism in stiff niches. Importantly, our observations indicated that lipid metabolism negatively impacted brain-metastasis free survival, while glutamine metabolism negatively impacted bone-metastasis free survival. Taken together, these findings provide new insights into the roles of primary tumor mechanical heterogeneity in metastasis organotropism and may have important implications for the development of new targeted therapies to prevent tumor cell metastasis into specific organs. |
| Rights: | All rights reserved |
| Access: | open access |
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