Project description:Transcriptomic analyses of early-stage brain metastatic cells reveals essential genes that promotes brain metastases, which are targetable.
Project description:The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the culprit molecular underpinnings, we designed an approach that combines sensitivity to drugs with an integrated systems-biology characterization. Sensitivity to inhibitors of the ERBB family of receptor tyrosine kinases correlated with their overexpression, suggesting a causative link. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to oncogenic signaling hubs including evolutionary conserved STAT3. Indeed, inhibition of ERBB blocked phosphorylation of STAT3 and arrested cancer cells. Blockade of ERBB signaling prevented tumor growth in a xenograft model and resulted in recovery of MHC-I gene expression. This link between the hyperactive ERBB-STAT3 axis and decreased MHC-I mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and lets us propose a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD.
Project description:The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. On one hand, hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. On the other hand, an upstreaming acute interleukin-6 (IL6) / signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte IL6 receptor (IL6R) deficiency and STAT3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL6/STAT3/MR/FGF21 signaling axis that mediates heart-liver crosstalk during MI. Targeting the signaling axis and the crosstalk may provide novel strategies to treat MI and heart failure.
Project description:To define the impact of STAT3-deletion on gene expresssion in primary and metastatic small cell lung cancer Gene expression was defined for cell lines derived from primary or liver metastases from independent mice by RNA-Seq
Project description:Initial screening for potential metastases suppressors down regulated by methylation was performed using lung cancer cell line models specific for site-specific metastasation. Gene expression profiling and qRT-PCR validations were conducted on tumor tissues from primary lung cancer (LC) and brain metastasis. HERC5 was further characterized for the methylation pattern.
Project description:Uveal melanoma (UM) with an inflammatory phenotype, characterized by infiltrating leukocytes and increased human leukocyte antigen (HLA) expression, carry an increased risk of death due to metastases. These tumors shoud be ideal for T-cell based therapies, yet it is not clear why prognostically-infaust tumors have a high HLA expression. We set out to determine whether the level of HLA molecules in UM is associated with other genetic factors, HLA transcriptional regulators, or microenvironmental factors. 28 enucleated UM were used to study HLA class I and II expression, and several regulators of HLA by immunohistochemistry, PCR microarray, qPCR and chromosome SNP-array. Fresh tumor samples of eight primary UM and four metastases were compared to their corresponding xenograft in SCID mice, using a PCR microarray and SNP array. Increased expression levels of HLA class I and II showed no dosage effect of chromosome 6p, but, as expected, were associated with monosomy of chromosome 3. Increased HLA class I and II protein levels were positively associated with their gene expression and with raised levels of the peptide-loading gene TAP1, and HLA transcriptional regulators IRF1, IRF8, CIITA, and NLRC5, revealing a higher transcriptional activity in prognostically-bad tumors. Implantation of fresh human tumor samples into SCID mice led to a loss of infiltrating leukocytes, and to a decreased expression of HLA class I and II genes , and their regulators. Our data provides evidence for a proper functioning HLA regulatory system in UM, offering a target for T-cell based therapies. NB: Here we show the PCR microarray (Illumina array).
Project description:In recent years, several approaches have been taken in the peptide-based immunotherapy of metastatic renal cell carcinoma (RCC), although little is known about HLA presentation on metastases compared to primary tumor and normal tissue of RCC. In this study we compared primary tumor, normal tissue and metastases with the aim of identifying similarities and differences between these tissues. We performed this comparison for two RCC patients on the level of the HLA ligandome using mass spectrometry and for three patients on the level of the transcriptome using oligonucleotide microarrays. The quantitative results show that primary tumor is more similar to metastasis than to normal tissue, both on the level of HLA ligand presentation and mRNA. We were able to characterize a total of 142 peptides in the qualitative analysis of HLA-presented peptides. Six of them were significantly overpresented on metastasis, among them a peptide derived from CD151; fourteen were overpresented on both primary tumor and metastasis compared to normal tissue, among them an HLA ligand derived from tumor protein p53. Thus, we could demonstrate that peptide-based immunotherapy might affect tumor as well as metastasis of RCC, but not healthy kidney tissue. Furthermore we were able to identify several peptides derived from tumor-associated antigens that are suitable for vaccination of metastatic RCC. Three clear cell renal cell carcinomas including autologous normal tissue and autologous metastasis were analyzed. This dataset is part of the TransQST collection.