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GSE15741
Mus musculus
6 Downloadable Samples
Description
Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here we addressed this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. A feature of metastasis-prone tumor cells that distinguished them from metastasis-incompetent tumor cells was plasticity in response to changes in their microenvironment. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in 3-dimensional culture that underwent epithelial-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This plasticity was entirely dependent upon the microRNA-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that microenvironmental cues direct tumor metastasis by regulating miR-200 expression.
Publication Title
Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression.
Sample Metadata Fields
Cell line
View Samples- Mus musculus, Homo sapiens
- 66 Downloadable Samples
Description
Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.
Publication Title
MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
Description
Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for spontaneous rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. Microarray data showed a 3-fold increase in interferon (IFN)- and a 2.7-fold increase in Fas ligand (FasL). There was a robust increase in transcripts (127 of 408 surveyed) from interferon (IFN)-stimulated genes and a marked decrease (in 40 of 192 surveyed) in the expression of cell-cycle-associated genes. Non-microarray data confirmed that IFN, FasL and CD8+ T cells but not perforin or TNF were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthsis). IFN and FasL did not target tumor cells directly as the majority of SPLNX IFNR1-/- mice and Fas-defective lpr mice failed to eliminate ocular E.G7-OVA tumors that expressed Fas and IFNR1. Bone marrow chimeras showed that immune cell expression of IFNR1 and Fas was critical and that SPLNX increased the frequency of activated macrophages within ocular tumors in an IFN- and Fas/FasL-dependent manner. Rejection of intraocular tumors was associated with increased ocular mRNA expression of several inflammatory genes including FasL, NOS2, CXCL2 and T-bet. Our data support a model in which IFN- and Fas/FasL-dependent activation of intratumoral macrophage by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis. The immunosuppressive mechanisms which maintain ocular IP likely interfere with the interaction between CD8+ T cells and macrophage to limit immunosurveillance of intraocular tumors.
Publication Title
Splenectomy promotes indirect elimination of intraocular tumors by CD8+ T cells that is associated with IFNγ- and Fas/FasL-dependent activation of intratumoral macrophages.
Sample Metadata Fields
Specimen part, Treatment
View Samples