Project description:Liposarcoma is a type of soft tissue sarcoma, exhibiting poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, emphasizing the need to understand this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. Our study demonstrates that all xenografts recapitulate morphologic and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability is directly correlated with disease specific survival of liposarcoma patients. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multi-kinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. One-color arrays: Vehicle vs combination (rapamycin & sorafenib) treatment for 2 separate dedifferentiated liposarcoma xenografts. Two-color arrays: Comparison of patient tumor, several passages of xenograft generated from that tumor, and cells cultured from xenografted tumors.
Project description:Notch signaling is an emerging regulator of liposarcoma (LPS) but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favors tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that are increased in LPS EVs of both species, including endotrophin as a biomarker of LPS. Functional analysis supports a role of LPS EVs in regulating gene expression and behaviors of endothelial cells in TME. Together, these data demonstrate that in addition to its known function in driving tumorigenesis, Notch signaling also regulates TME through EV secretion.
Project description:Notch signaling is an emerging regulator of liposarcoma (LPS) but its role in mediating communication with the tumor microenvironment (TME) is unclear. Here, we investigate how Notch activation (NICD overexpression) alters proteomes of LPS-derived extracellular vesicles (EVs). We used quantitative mass spectrometry to profile EV proteome in multiple contexts: cultured LPS cells, LPS tumor, circulating EVs of LPS-bearing mice and human LPS samples. We found that Notch signaling increases the secretion of EV proteins that favors tumor progression and metastasis but suppresses immune responses in murine LPS cells. Overlapping murine and human LPS data identifies 18 proteins that are increased in LPS EVs of both species, including endotrophin as a biomarker of LPS. Functional analysis supports a role of LPS EVs in regulating gene expression and behaviors of endothelial cells in TME. Together, these data demonstrate that in addition to its known function in driving tumorigenesis, Notch signaling also regulates TME through EV secretion.
Project description:Liposarcoma is a type of soft tissue sarcoma, exhibiting poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, emphasizing the need to understand this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. Our study demonstrates that all xenografts recapitulate morphologic and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability is directly correlated with disease specific survival of liposarcoma patients. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multi-kinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile.
Project description:Germinal center (GC) B cells have been presented as the cell-of-origin of diffuse large B-cell lymphoma (DLBCL), and these cells can be functionally targeted with the use of Cgamma1-cre mice (Cg1cre) in wich the expression of Cre recombinase is induced by transcription of the Ig gamma1 constant region gene segment. Here, we aimed to develop and characterize novel immunocompetent multi-lesion mouse models of DLBCL that, by triggering genetic alterations specifically in GC B cells, recapitulate relatively fast the molecular, cellular and tumor microenvironment of aggressive human DLBCL.
Project description:Germinal center (GC) B cells have been presented as the cell-of-origin of diffuse large B-cell lymphoma (DLBCL), and these cells can be functionally targeted with the use of Cgamma1-cre mice (Cg1cre) in wich the expression of Cre recombinase is induced by transcription of the Ig gamma1 constant region gene segment. Here, we aimed to develop and characterize novel immunocompetent multi-lesion mouse models of DLBCL that, by triggering genetic alterations specifically in GC B cells, recapitulate relatively fast the molecular, cellular and tumor microenvironment of aggressive human DLBCL.
Project description:Germinal center (GC) B cells have been presented as the cell-of-origin of diffuse large B-cell lymphoma (DLBCL), and these cells can be functionally targeted with the use of Cgamma1-cre mice (Cg1cre) in wich the expression of Cre recombinase is induced by transcription of the Ig gamma1 constant region gene segment. Here, we aimed to develop and characterize novel immunocompetent multi-lesion mouse models of DLBCL that, by triggering genetic alterations specifically in GC B cells, recapitulate relatively fast the molecular, cellular and tumor microenvironment of aggressive human DLBCL.
