Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Jing  Yang
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $345,584
Funding agency: National Cancer Institute

Breast tumors are often identified by manual palpation due to their apparent “hardness” compared to normal
tissue. The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue
stiffness and correlates with distant metastasis and poor outcome. Recent studies show that increasing matrix
stiffness can induce a malignant phenotype in cultured human mammary organoids, suggesting that
mechanical properties of extracellular matrix directly regulate tumor metastasis. However, how mechanical
forces are translated into biochemical signals to promote tumor invasion and metastasis is largely unknown.
Our preliminary studies found that rigid matrix stiffness activates a novel mechanotransduction pathway to
induce Epithelial-Mesenchymal Transition (EMT) and promote tumor metastasis. We therefore hypothesize
that mechanical forces activates the LYN kinase to allow the EMT-inducing transcription factor TWIST1 to
promote tumor invasion and metastasis. To test this hypothesis, we plan to 1) To elucidate the molecular
mechanism by which high tissue stiffness activates a novel mechanotransduction cascade to promote TWIST1
nuclear translocation and EMT; 2) To elucidate the novel molecular mechanism by which soft matrix stiffness
prevents TWIST1 nuclear translocation and inhibit EMT; 3) To determine the involvement of the Twist1
mechanotransduction pathway in promoting metastasis in vivo and in predicting human breast cancer
progression.

Terms: <3-D><3-Dimensional><3D><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Biochemical><Body Tissues><Breast Cancer><Breast Cancer Patient><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cell-Extracellular Matrix><Cellular Mechanotransduction><Collagen Fiber><Cytoplasm><Data><Dephosphorylation><Distant Cancer><Distant Metastasis><ECK gene><ECK protein><ECM><EPH receptor A2><EPHA2><EPHA2 gene><Ensure><Epithelium><Extracellular Matrix><Family><G3BP><G3BP1><G3BP1 gene><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Goals><Hardness><Homolog of Drosophila TWIST 1><Homolog of Drosophila TWIST1><Human><Intracellular Communication and Signaling><Invaded><JTK8><Kinases><LYN><LYN gene><Link><Malignant Breast Neoplasm><Malignant Cell><Mammary Cancer><Mammary Neoplasms><Mammary gland><Manuals><Mechanical Signal Transduction><Mechanosensory Transduction><Mesenchymal><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Neoplasm Metastasis><Nodule><Normal Tissue><Normal tissue morphology><Nuclear><Nuclear Translocation><Nucleus><Organoids><Outcome><Palpation><Pathway interactions><Phosphatases><Phosphohydrolases><Phosphomonoesterases><Phosphoric Monoester Hydrolases><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiological><Play><Protein Dephosphorylation><Protein Phosphorylation><Proteins><RNA Expression><Regulation><Research><Role><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><TWIST gene><TWIST1><TWIST1 gene><TYK2><Testing><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Factor TWIST><Transcription factor genes><Translating><Transphosphorylases><Tumor Cell Invasion><Tumor Invasion><Tumor Promotion><Work><arm><biological signal transduction><breast cancer progression><breast epithelium><cancer cell><cancer metastasis><cancer microenvironment><clinical significance><clinically significant><driving><in vivo><malignant breast tumor><malignant phenotype><mammary><mammary epithelium><mammary tumor><mechanical force><mechanical properties><mechanosensing><mechanotransduction><novel><pathway><prevent><preventing><reconstitute><reconstitution><recruit><response><social role><therapeutic target><three dimensional><transcription factor><tumor><tumor cell metastasis><tumor microenvironment><twist protein><v-YES-1 Yamaguchi Sarcoma Viral Related Oncogene Homolog>