Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 that associates with reduced breast cancer survival outcomes in multiple cohorts. Genetic modeling of this gain-of-function single nucleotide variant in mice revealed that it causally promoted breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and increased proliferative competence by targeting tumoral LRP1 receptors which repress metastasis-promoting genes. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. This variant stratified women in a large Swedish early-stage breast cancer cohort into those with 98% versus 78% distant-metastasis-free interval at 15 years after diagnosis. Our findings reveal that a commonly inherited genetic alteration predicts breast cancer survival and governs breast cancer metastasis—uncovering a hereditary basis underlying a prevalent cause of mortality.
Project description:To investigate the apoE isoform-dependent role of vascular mural cell (VMC)-LRP1, we generated VMC-specific LRP1 knockout mice (smLrp1-/-), followed by breeding these mice with either APOE3-targeted replacement (TR) or APOE4-TR mice We then performed gene expression profiling analysis using data obtained from RNA-seq of cortical samples from 4 different mouse models
Project description:In the present study, we analyzed single-cell multi-omics data from psoriasis patients and healthy individuals and found that more fibroblast-macrophage communication was present in the dermis of psoriasis lesions, exacerbating psoriasis progression. A natural product library was used to screen for a small molecule compound, celastrol, that could interfere with fibroblast-macrophage communication. It was demonstrated that celastrol targeted low-denisity lipoprotein receptor-related protein 1 (LRP1) to inhibit fibroblast secretion of CCL2 and inhibited psoriasis progression by reducing its recruitment to macrophages, thereby blocking communication between the two cells. Moreover, conditional knockdown of LRP1 by fibroblasts significantly improved psoriasis in mice, suggesting that LRP1 may be an important target for the treatment of psoriasis.
Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 that associates with reduced breast cancer survival outcomes in multiple cohorts. Genetic modeling of this gain-of-function single nucleotide variant in mice revealed that it causally promoted breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and increased proliferative competence by targeting tumoral LRP1 receptors which repress metastasis-promoting genes. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. This variant stratified women in a large Swedish early-stage breast cancer cohort into those with 98% versus 78% distant-metastasis-free interval at 15 years after diagnosis. Our findings reveal that a commonly inherited genetic alteration predicts breast cancer survival and governs breast cancer metastasis—uncovering a hereditary basis underlying a prevalent cause of mortality.
Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 that associates with reduced breast cancer survival outcomes in multiple cohorts. Genetic modeling of this gain-of-function single nucleotide variant in mice revealed that it causally promoted breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and increased proliferative competence by targeting tumoral LRP1 receptors which repress metastasis-promoting genes. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. This variant stratified women in a large Swedish early-stage breast cancer cohort into those with 98% versus 78% distant-metastasis-free interval at 15 years after diagnosis. Our findings reveal that a commonly inherited genetic alteration predicts breast cancer survival and governs breast cancer metastasis—uncovering a hereditary basis underlying a prevalent cause of mortality.
Project description:Identifying patients at risk for metastatic relapse is a critical need in oncology. We identified a common missense germline variant in PCSK9 that associates with reduced breast cancer survival outcomes in multiple cohorts. Genetic modeling of this gain-of-function single nucleotide variant in mice revealed that it causally promoted breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and increased proliferative competence by targeting tumoral LRP1 receptors which repress metastasis-promoting genes. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. This variant stratified women in a large Swedish early-stage breast cancer cohort into those with 98% versus 78% distant-metastasis-free interval at 15 years after diagnosis. Our findings reveal that a commonly inherited genetic alteration predicts breast cancer survival and governs breast cancer metastasis—uncovering a hereditary basis underlying a prevalent cause of mortality.