Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning

Watson, Adam W.; Grant, Adam; Parker, Sara S.; Hill, Samantha M.; Whalen, Michael B.; Chakrabarti, Jayati; Harman, Michael W.; Roman, Mackenzie R.; Forte, Brittany L.; Gowan, Cody; Castro-Portuguez, Raúl; Stolze, Lindsey K; Franck, Christian; Cusanovich, Darren A.; Zavros, Yana; Padi, Megha; Romanoski, Casey E.; Mouneimne, Ghassan

doi:10.1016/j.celrep.2021.109293

Cited by 44 publications

(40 citation statements)

References 70 publications

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“…Previous studies have indicated that tissue stiffness is crucial for metastasis. Increasing tissue stiffness in primary tumors enhances the metastatic potential of cancer cells in HCC [ 19 , 63 ], lung cancer [ 14 , 20 , 22 ], and mammary cancer [ 26 , 53 , 54 , 60 , 64 , 65 ]. Matrix stiffening affects not only cancer cells but also non-cancerous cells during metastasis.…”

Section: Cancer Progression Regulated By Matrix Stiffnessmentioning

confidence: 99%

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors

Ishihara

Haga

2022

Cancers

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Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger mechanotransduction, the conversion of mechanical cues such as stiffness of the matrix to biochemical signaling in the cells, and as a result determine the cellular phenotypes of cancer and stromal cells in tumors. Transcription factors are key molecules for these processes, as they respond to matrix stiffness and are crucial for cellular behaviors. The Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is one of the most studied transcription factors that is regulated by matrix stiffness. The YAP/TAZ are activated by a stiff matrix and promotes malignant phenotypes in cancer and stromal cells, including cancer-associated fibroblasts. In addition, other transcription factors such as β-catenin and nuclear factor kappa B (NF-κB) also play key roles in mechanotransduction in cancer tissues. In this review, the mechanisms of stiffening cancer tissues are introduced, and the transcription factors regulated by matrix stiffness in cancer and stromal cells and their roles in cancer progression are shown.

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Section: Cancer Progression Regulated By Matrix Stiffnessmentioning

confidence: 99%

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors

Ishihara

Haga

2022

Cancers

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“…On the other hand, single primary breast cancer cells are very soft (~300 Pa), similar to the CNS cells described above [81]. It is conceivable that tumor cells with different mechanical conditioning target different metastatic sites, as shown for breast cancer cells [82]. Since it is known that cells have a high affinity for stiffer substrates [17], it is plausible that tumor cells demonstrate a durotactic activity for stiffer white matter tracts and blood vessels in the brain.…”

Section: Discussionmentioning

confidence: 83%

Brain and Breast Cancer Cells with PTEN Loss of Function Reveal Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Utilizing 3D Scaffolds and Aligned Microfiber Tracts

Wieland

Strissel

Schorle

et al. 2021

Cancers

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Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.

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“…This stiff ECM architecture increases cell migration, providing a leading "highway" and promoting cellular contraction, and it obstructs drug delivery due to the elevated interstitial fluid pressure [72]. It has been shown recently that conditioning to ECM stiffness in breast cancer favors bone metastasis [73,74]. Triple-negative breast cancer shows increased deposition of collagen and enhanced invasion of cancer-associated fibroblasts [75,76].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Response to Acidosis Reveals Its Contribution to Bone Metastasis in Breast Cancer Cells

Yamagata

Freire

Villarinho

et al. 2022

Cells

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Bone is the most common site of metastasis in breast cancer. Metastasis is promoted by acidosis, which is associated with osteoporosis. To investigate how acidosis could promote bone metastasis, we compared differentially expressed genes (DEGs) in MDA-MB-231 cancer cells in acidosis, bone metastasis, and bone metastatic tumors. The DEGs were identified using Biojupies and GEO2R. The expression profiles were assessed with Morpheus. The overlapping DEGs between acidosis and bone metastasis were compared to the bulk of the DEGs in terms of the most important genes and enriched terms using CytoHubba and STRING. The expression of the genes in this overlap filtered by secreted proteins was assessed in the osteoporosis secretome. The analysis revealed that acidosis-associated transcriptomic changes were more similar to bone metastasis than bone metastatic tumors. Extracellular matrix (ECM) organization would be the main biological process shared between acidosis and bone metastasis. The secretome genes upregulated in acidosis, bone metastasis, and osteoporosis-associated mesenchymal stem cells are enriched for ECM organization and angiogenesis. Therefore, acidosis may be more important in the metastatic niche than in the primary tumor. Acidosis may contribute to bone metastasis by promoting ECM organization. Untreated osteoporosis could favor bone metastasis through the increased secretion of ECM organization proteins.

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Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning

Cited by 44 publications

References 70 publications

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors

Brain and Breast Cancer Cells with PTEN Loss of Function Reveal Enhanced Durotaxis and RHOB Dependent Amoeboid Migration Utilizing 3D Scaffolds and Aligned Microfiber Tracts

Transcriptomic Response to Acidosis Reveals Its Contribution to Bone Metastasis in Breast Cancer Cells

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