TL1A priming induces a multi-cytokine Th9 cell phenotype that promotes robust allergic inflammation in murine models of asthma.

Multi-cytokine-producing Th9 cells secrete IL-9 and type 2 cytokines and mediate mouse and human allergic inflammation. However, the cytokines that promote a multi-cytokine secreting phenotype have not been defined. Tumor necrosis factor superfamily member TL1A signals through its receptor DR3 to increase IL-9. Here we demonstrate that TL1A increases expression of IL-9 and IL-13 co-expressing cells in murine Th9 cell cultures, inducing a multi-cytokine phenotype. Mechanistically, this is linked to histone modifications allowing for increased accessibility at the Il9 and Il13 loci. We further show that TL1A alters the transcription factor network underlying expression of IL-9 and IL-13 in Th9 cells and increases binding of transcription factors to Il9 and Il13 loci. TL1A-priming enhances the pathogenicity of Th9 cells in murine models of allergic airway disease through the increased expression of IL-9 and IL-13. Lastly, in both chronic and memory-recall models of allergic airway disease, blockade of TL1A signaling decreases the multi-cytokine Th9 cell population and attenuates the allergic phenotype. Taken together, these data demonstrate that TL1A promotes the development of multi-cytokine Th9 cells that drive allergic airway diseases and that targeting pathogenic T helper cell-promoting cytokines could be an effective approach for modifying disease.

MYC oncogene elicits tumorigenesis associated with embryonic, ribosomal biogenesis, and tissue-lineage dedifferentiation gene expression changes.

MYC is a transcription factor frequently overexpressed in cancer. To determine how MYC drives the neoplastic phenotype, we performed transcriptomic analysis using a panel of MYC-driven autochthonous transgenic mouse models. We found that MYC elicited gene expression changes mostly in a tissue- and lineage-specific manner across B-cell lymphoma, T-cell acute lymphoblastic lymphoma, hepatocellular carcinoma, renal cell carcinoma, and lung adenocarcinoma. However, despite these gene expression changes being mostly tissue-specific, we uncovered a convergence on a common pattern of upregulation of embryonic stem cell gene programs and downregulation of tissue-of-origin gene programs across MYC-driven cancers. These changes are representative of lineage dedifferentiation, that may be facilitated by epigenetic alterations that occur during tumorigenesis. Moreover, while several cellular processes are represented among embryonic stem cell genes, ribosome biogenesis is most specifically associated with MYC expression in human primary cancers. Altogether, MYC's capability to drive tumorigenesis in diverse tissue types appears to be related to its ability to both drive a core signature of embryonic genes that includes ribosomal biogenesis genes as well as promote tissue and lineage specific dedifferentiation.

Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers.

BACKGROUND AND AIMS: Vascular invasion (VI) is a critical risk factor for HCC recurrence and poor survival. The molecular drivers of vascular invasion in HCC are open for investigation. Deciphering the molecular landscape of invasive HCC will help identify therapeutic targets and noninvasive biomarkers. APPROACH AND RESULTS: To this end, we undertook this study to evaluate the genomic, transcriptomic, and proteomic profile of tumors with VI using the multiplatform cancer genome atlas (The Cancer Genome Atlas; TCGA) data (n = 373). In the TCGA Liver Hepatocellular Carcinoma cohort, macrovascular invasion was present in 5% (n = 17) of tumors and microvascular invasion in 25% (n = 94) of tumors. Functional pathway analysis revealed that the MYC oncogene was a common upstream regulator of the mRNA, miRNA, and proteomic changes in VI. We performed comparative proteomic analyses of invasive human HCC and MYC-driven murine HCC and identified fibronectin to be a proteomic biomarker of invasive HCC (mouse fibronectin 1 [Fn1], P = 1.7 × 10-11 ; human FN1, P = 1.5 × 10-4 ) conserved across the two species. Mechanistically, we show that FN1 promotes the migratory and invasive phenotype of HCC cancer cells. We demonstrate tissue overexpression of fibronectin in human HCC using a large independent cohort of human HCC tissue microarray (n = 153; P < 0.001). Lastly, we showed that plasma fibronectin levels were significantly elevated in patients with HCC (n = 35; mean = 307.7 µg/mL; SEM = 35.9) when compared to cirrhosis (n = 10; mean = 41.8 µg/mL; SEM = 13.3; P < 0.0001). CONCLUSIONS: Our study evaluates the molecular landscape of tumors with VI, identifying distinct transcriptional, epigenetic, and proteomic changes driven by the MYC oncogene. We show that MYC up-regulates fibronectin expression, which promotes HCC invasiveness. In addition, we identify fibronectin to be a promising noninvasive proteomic biomarker of VI in HCC.