Stiffness-related mitochondria transfer promotes tumor progression through metabolic reprogramming
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE311895 | GEO | 2025/12/04
REPOSITORIES: GEO
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Project description:The mechanical microenvironment of primary breast tumors plays a substantial role in promoting tumor progression. While the transitory response of cancer cells to pathological stiffness in their native microenvironment has been well described, it is unclear whether mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes in absentia. Here, we show that primary tumor stiffness promotes stable yet non-genetically heritable phenotypes in breast cancer cells. This “mechanical memory” instructs cancer cells to adopt and maintain increased cytoskeletal dynamics, traction force, and 3D invasion in vitro, in addition to promoting osteolytic bone metastasis in vivo. We established a “mechanical conditioning score” comprised of mechanically-regulated genes as a proxy measurement of tumor stiffness response, and we show that it is associated with bone metastasis in patients. Using a discovery approach, we mechanistically traced mechanical memory in part to ERK-mediated mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver. This combination of traits allows for the stable transactivation of osteolytic target genes which persists after cancer cells disseminate from their activating microenvironment. Using genetic, epigenetic, and functional approaches, RUNX2-mediated mechanical memory can be stimulated, repressed, selected, or extended. In concert with previous studies detailing how biochemical properties of the primary tumor stroma influence distinct metastatic phenotypes, the impact of local biomechanical properties we present here support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern cell behavior in the metastatic microenvironment.
2021-07-01 | GSE127887 | GEO
Project description:Tissue mechanical homeostasis, the concept that cells sense mechanical properties and alter rates of ECM synthesis, assembly and degradation, is of broad interest in biology and medicine, but there is little direct support or insight into mechanisms. Tissue mechanical properties such as elasticity and stiffness are determined primarily by the extracellular matrix (ECM). We therefore set out to test the mechanical homeostasis hypothesis by developing mutations in the mechanosensitive protein talin1 that alter cells’ sensing of ECM stiffness. We identified the side-to-side interaction between talin1 rod domain helix bundles 1 and 2 (R1 and R2) as a novel mechanosensitive site. Mutations that decrease the affinity of the interaction result in a leftward shift in cellular stiffness sensing curves, enabling cells to spread and exert tension on softer substrates. Opening of the R1-R2 interface promotes binding of the Arp2/3 subunit ArpC5L, which is required for the altered stiffness sensing. Introduction of these talin mutations into mice resulted in softer tissue in the ascending aorta with less fibrillar collagen and rupture under lower pressure ex vivo. Together, these results demonstrate that altering cellular stiffness sensing results in altered ECM deposition, tissue stiffness and strength, thus providing direct support for the mechanical homeostasis hypothesis. These results also identify a novel mechanosensitive interaction in the talin rod domain that contributes to this mechanism.
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Project description:The mechanical properties of solid tumors influence tumor cell phenotype and ability to invade into surrounding tissues. Using bioengineered scaffolds to provide a matrix microenvironment for patient-derived glioblastoma (GBM) spheroids, this study demonstrates that a soft, brain-like matrix induces GBM cells to shift to a glycolysis-weighted metabolic state which supports invasive behavior. We first show that orthotopic murine GBM tumors are stiffer than peri-tumoral brain tissues, but tumor stiffness is heterogenous where tumor edges are softer than the tumor core. Then, we developed three-dimensional scaffolds with µ-compressive moduli resembling either stiffer, tumor core or softer, peri-tumoral brain tissue. We demonstrate that the softer matrix microenvironment induces a shift in GBM cell metabolism toward glycolysis which manifests in lower proliferation rate and increased migration activities. Finally, we show that these mechanical cues are transduced from the matrix via CD44 and integrin receptors to induce metabolic and phenotypic changes in cancer cells.
2023-08-02 | GSE239610 | GEO
Project description:Cells interact with their mechanical environment and respond in consequence. Mechanical cues can have a wide range of influences on cell behaviour, ranging from guidance of differentiation and cell fate to immune activation. The impact of substrate stiffness on primary macrophages - a key player in innate immunity and inflammation - had not been previously studied. We prepared bone marrow-derived macrophage cultures from adult rat hematopoietic stem cells exposed to M-CSF, and cultured these on polyacrylamide substrates of controlled stiffness (ranging from 50 to 0.1 kPa shear modulus, covering the range found in physiological tissues) for 3 days. The RNA from these cells was then extracted and sequenced.
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Project description:Mechanical feedback from the tumor microenvironment regulates an array of processes underlying cancer biology. Routine culture and adaptation of cancer cell lines to unnaturally rigid plastic or glass substrates leads to profound changes in their growth, metastatic potential and potentially chemotherapeutic response. Microarray studies were conducted to probe the impact of substratum stiffness on the regulation of genetic pathways in mammary tumor cells, and immortalized cancer cell lines, that modulate sensitivity and resistance towards clinically-approved chemotherapeutics We used microarrays to detail the global programme of gene expression underlying cellular response to substrates of different mechanical stiffness.
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Project description:Breast tumor stiffness instructs bone metastasis via mechanical memory
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Project description:Intratumor heterogeneity associates with poor patient outcome. Stromal stiffening also accompanies cancer. Whether cancers demonstrate stiffness heterogeneity, and if this is linked to tumor cell heterogeneity remains unclear. We developed a method to measure the stiffness heterogeneity in human breast tumors that quantifies the stromal stiffness each cell experiences and permits visual registration with biomarkers of tumor progression. We present Spatially Transformed Inferential Force Map (STIFMap) which exploits computer vision to precisely automate atomic force microscopy (AFM) indentation combined with a trained convolutional neural network to predict stromal elasticity with micron-resolution using collagen morphological features and ground truth AFM data. We registered high-elasticity regions within human breast tumors colocalizing with markers of mechanical activation and an epithelial-to-mesenchymal transition (EMT). The findings highlight the utility of STIFMaps to assess mechanical heterogeneity of human tumors across length scales from single cells to whole tissues and implicates stromal stiffness in tumor cell heterogeneity.
2023-04-30 | GSE179983 | GEO
Project description:Remodeling and increased stiffness of the extracellular matrix is a hallmark of solid cancers and contributes to tumor progression through increased proliferation, survival and migration. Mechanotransduction, the process in which cells sense and transduce mechanical signals, can result in transcriptional changes that in turn alter cellular behavior. In vitro culturing of MCF10ACA1a (CA1a) breast cancer cells on polyacrylamide-based hydrogels of variable stiffness revealed drastic changes in morphology, indicating a stiffness dependent induction of a malignant phenotype. We used DNA microarray to characterize the transcriptome of CA1a cells on low (400 Pa) and high (5000 Pa) stiffness, corresponding to the stiffness of normal breast and breast cancer, respectively.
2023-03-13 | GSE205817 | GEO
Project description:Cells sense the biophysical properties of the surrounding microenvironment. In particular, the stiffness of the extracellular milieu can be interrogated by cells and integrated through mechanotransduction. Many cellular processes (like proliferation, migration, or differentiation) depend on the mechanical status of the cell (being largely dictated by actomyosin-dependent intracellular contractility), which in turn is influenced by the mechanical properties of the microenvironment. In this study, we explored the influence of substrate stiffness on the proteome of undifferentiated human umbilical cord matrix mesenchymal stem/stromal cells (hUCM-MSCs). The relative abundance of several identified proteins suffered significant changes when comparing between substrates. Interestingly, many of such proteins are related to the regulation of the actin cytoskeleton, a main player of mechanotransduction and cell physiology in response to mechanical cues.
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