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Mechanotransduction regulates adipose estrogen output and its impact on tumor cell growth

ABSTRACT: Adipose stromal cells (ASCs) are the primary source of local estrogens in adipose tissue, aberrant production of which promotes estrogen receptor-positive (ER+) breast cancer. Here we show that extracellular matrix (ECM) rigidity and cell contractility are two opposing determinants for estrogen output of ASCs. Using synthetic ECMs and elastomeric micropost arrays with tunable rigidity, we find that increasing matrix compliance induces transcription of aromatase, a rate-limiting enzyme in estrogen biosynthesis. This mechanical cue is transduced sequentially by Discoidin Domain Receptor 1 (DDR1), c-Jun N-terminal kinase 1 (JNK1), and phosphorylated JunB, which binds to and activates two breast cancer-associated aromatase promoters. In contrast, elevated cell contractility due to actin stress fiber formation dampens aromatase transcription. Mechanically stimulated stromal estrogen production enhances estrogen-dependent transcription in ER+ tumor cells and promotes their growth. This novel mechanotransduction pathway underlies communications between ECM, stromal hormone output, and cancer cell growth within the same microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44811 | GEO | 2013/03/04

SECONDARY ACCESSION(S): PRJNA191906

REPOSITORIES: GEO

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Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.

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Mechanotransduction regulates adipose estrogen output and its impact on tumor cell growth

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