Project description:The ability of cancer cells to switch phenotype in response to a dynamic intra-tumor microenvironment is a major barrier to effective therapy. In melanoma, down-regulation of the lineage addiction oncogene MITF (Microphthalmia-associated transcription factor) is a hallmark of the proliferative-to-invasive phenotype switch. Yet how MITF promotes proliferation and suppresses invasion is poorly understood. Here we show that expression of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) is activated by MITF, but suppressed by the stress-responsive transcription factor ATF4. SCD expression is required for MITF-positive melanoma cell proliferation,. By contrast, MITF-low cells express reduced levels of SCD and are insensitive to its inhibition, indicating that cell phenotype dictates response to drugs targeting lipid metabolism. Since SCD suppresses inflammatory signalling and ATF4 expression, the results identify a positive feedback-loop that can maintain an invasive phenotype, uncover a key role for MITF and ATF4 in metabolic reprograming, and reveal fatty acid composition as a driver of melanoma phenotype-switching.
Project description:Hepatocellular carcinoma (HCC) is a highly heterogenous disease associated with an equally dynamic tumor microenvironment (TME). We generated somatic HCC mouse models bearing clinically-relevant oncogenic driver combinations that faithfully recapitulated different human HCC subclasses. Using WES data, we explored the tumor mutation frequencies between models and compared them with human datasets.
Project description:Hepatocellular carcinoma (HCC) is a highly heterogenous disease associated with an equally dynamic tumor microenvironment (TME). We generated somatic HCC mouse models bearing clinically-relevant oncogenic driver combinations that faithfully recapitulated different human HCC subclasses. Using WES data, we explored the tumor mutation frequencies between models and compared them with human datasets.
Project description:Tumor initiation and progression are critically dependent on interaction of cancer cells with their cellular and extracellular microenvironment. Alterations in the composition, integrity, and mechanical properties of the extracellular matrix (ECM) dictate tumor processes including proliferation, migration, and invasion. Also in primary liver cancers, consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the dysregulation of the extracellular environment by liver fibrosis and tumor desmoplasia is pertinent. Yet, in-depth characterization of liver cancer ECM and underlying tumor-promoting mechanisms remain largely unknown. Herein, we used an integrative molecular and mechanical approach to extensively characterize the ECM of HCC and CCA tumors by utilizing decellularization techniques. We identified a myriad of ECM-related proteins in both tumor and adjacent liver tissue, highlighting the complexity of the primary liver cancer matrisome. The differences in ECM protein abundance result in divergent mechanical properties on a macro- and micro-scale that is tumor-type specific. Furthermore, we employed the decellularized tumor ECM to create a tumor-specific hydrogel that support patient-derived tumor organoids. This provides a new avenue for personalized medicine by combining patient-derived tumor ECM and cancer cells. Taken together, this study provides better understanding of alterations to key aspects of the ECM that occur during primary liver cancer development.
Project description:Hepatocellular carcinoma (HCC) is a highly heterogenous disease associated with an equally dynamic tumor microenvironment (TME). We generated somatic HCC mouse models bearing clinically-relevant oncogenic driver combinations that faithfully recapitulated different human HCC subclasses. Using scRNA-seq data, we explored changes in the TME to characterize phenotypic differences between immune populations.
Project description:Hepatocellular carcinoma (HCC) is a highly heterogenous disease associated with an equally dynamic tumor microenvironment (TME). We generated somatic HCC mouse models bearing clinically-relevant oncogenic driver combinations that faithfully recapitulated different human HCC subclasses. Using RNA-seq data, we explored changes in the TME and dissected cancer cell intrinsic shapers of the TME.
Project description:Macrophages found in the tumor microenvironment (TME) are causally linked with disease development and progression. Different phenotypes of macrophages have been described, including the M1-like pro-inflammatory/anti-tumor phenotype or the M2-like anti-inflammatory/pro-tumor phenotype. Here we present the first single cell transcriptomic analysis on human prostate cancer (PCa)-resident macrophages.
2020-06-01 | GSE135520 | GEO
Project description:Discover driver genes with somatic mutations for heterogeneous tumor image phenotype in pancreatic cancer
Project description:Ablative RT results in increased expression of CCL2 within the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) and also increased recruitment of CD45+CD11b+Ly6Chi inflammatory monocytes/macrophages. This increase in CCL2 expression and recruitment of inflammatory monocytes/macrophages is a mechanism of resistance to the anti-tumor effects of ablative radiotherapy (RT). We used microarrays to study changes in gene expression patterns of inflammatory monocytes/macrophages sorted from the tumor microenvironment after ablative RT in a subcutenous model of pancreatic adenocarcinoma. From this, we identified 8 genes with an absolute fold change of expression equal to or greater than 2 with a false discovery rate equal to or less than 25 %. A pancreatic cancer tumor cell line derived from spontaneously arising tumors in KrasLSL-G12D/+, Trp53LSL-R172H/+, Pdx1-Cre (KPC) mice was subcutaneously implanted into 8 week old female C57BL/6 and allowed to grow for 14 days. After 14 days, 4 mice received 20 Gy of radiation, and 4 mice received a sham treatment. One day post treatment, tumors were harvested, and inflammatory monocytes/macrophages were isolated using flow sorting based on a surface expression phenotype of CD45+ CD11b+ Ly6Chi. From this cell population, total RNA was extracted for creation of cDNA and hybridization on Affymetrix microarrays. From the microarrays, a set of genes associated with radiation treatment of PDAC was identified.
Project description:Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system progenitor cells. MYCN and ALK are driver oncogenes both of which are specifically expressed during early neurogenesis. This is in line with the assumption that neuroblastoma arises through disruption of normal developmental processes. MYCN has a broad impact on the tumor phenotype; however, the details of the MYCN driven oncogenic program are far from clear. In order to gain further insight into the role of gene expression during neuroblastoma initiation and progression, we evaluated gene expression profiles of hyperplastic ganglia and tumors isolated from MYCN transgenic mice.
