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Transcriptome analysis of pancreatic cancer patients with low and high metabolic tumor volume (MTV)

ABSTRACT: Transcriptome wide-comparison between MTV-low and -high groups was performed with three types: 1) cancer to normal site ratio, cancer site, and normal site. Among three types of comparison, the cancer-to-normal site ratio was the most informative. 211 genes were generally upregulated, and 166 genes were downregulated in the MTV-high group compared to the MTV-low group. Of 211 upregulated gens, 44 showed more than a 2-fold difference and statistical significance. On the other hand, of 166 downregulated genes, 56 showed more than a 2-fold difference and statistical significance. In functional annotation analysis, the GO terms of the upregulated genes were enriched to Wnt signaling (GO: 0035567, 0060070, 0060071), sister chromatid cohesion (GO: 0007062), and cell division (GO: 0000278, 0051301) trends (Figure 1E-a), whereas those of the downregulated genes were enriched to rRNA processing (GO: 0006364), translation (GO: 0006412, 0006413), nuclear-transcribed mRNA catabolic process (GO: 0000184) trends (Figure 1E-b). 28 upregulated genes belonged to Wnt signaling or Cell division, while 22 downregulated genes belonged to rRNA processing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192647 | GEO | 2024/05/22

REPOSITORIES: GEO

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Project description:We analyzed global genome-wide transcriptional response of bone marrow derived macrophages (BMDM) to tunicamycin (TM). This analysis demonstrated that TM treatment changed the expression of 1,426 genes in WT BMDM and 1,075 genes in 4KO BMDM ( Casp1-/-Casp8-/-Casp11-/-Ripk3-/- ) (2-fold cut-off, p<0.05). Among differentially-expressed genes, all downregulated 759 genes were downregulated to similar levels in both WT and 4KO BMDM after TM treatment. However, 667 genes activated by TM treatment were globally upregulated to significantly higher levels in WT, compared to 4KO BMDM which is consistent with previous findings of a muted macrophage responses to triggers in cells lacking CASP8. Next we used gene set enrichment analysis to annotate pathways deregulated by TM in BMDM and compared down-regulated and upregulated gene sets in BMDM to their expression in liver resident Mf, Kupffer cells, at homeostatic conditions in vivo. The most prominently down-regulated pathways in BMDM after TM treatment were cell cycle, DNA replication, and metabolism pathways (normalized enrichment score (NES) =-8.5, -7.9, -7.1, respectively, FDR<1e-4,). Importantly, the gene sets constituting downregulated pathways in TM-treated BMDM were highly expressed in KC in vivo at homeostatic levels (NES= 8.7, 10.5, 6.6 , FDR<1e-4), suggesting the lack of phenotypic similarity between TM-treated BMDM and KC for this set of pathways. However, this same analysis showed that the most prominently enriched pathways in BMDM after TM treatment were pathways related to innate and adaptive immune signaling, cytokine signaling and mitogen-activated protein kinase signaling (NES =8.7, 6.4, 6.9, 3.2, respectively , FDR<1e-4). The gene set enrichment analysis for this set of genes demonstrated that in KC at homeostatic conditions, these same genes are also highly enriched (NES=12.6, 9.8, 7.1, 4.5 , FDR<1e-4), suggesting that for upregulated gene sets, TM treatment drives BMDM in vitro to transcriptomic phenotype similar to that observed in KC in vivo at homeostatic conditions.

Project description:To discover RBPs with increased insolubility in a human ALS model, we applied a well established dual-SMAD inhibition-based protocol (Fang et al., 2019; Markmiller et al., 2021; Markmiller et al., 2018; Martinez et al., 2016) to generate iPSC-MN from six control iPSC lines, from four iPSC lines originating from two sALS patients, and from two iPSC lines originating from fALS patients with pathogenic variants in the TARDBP gene (Table S1; Figure S1A). No difference in differentiation capacity was observed (Figure S1B-G), resulting in average 40% ISL1+ MN (Figures S1G), comparable to numbers observed in large scale MN differentation studies (Baxi et al., 2022). The susceptibility of ALS MN to sodium arsenite-induced stress was not changed (Figure S1H and I). Next, we asked which proteins exhibit an increased insolubility in our ALS iPSC-MN. We fractioned iPSC- MN by lysis in radio-immunoprecipitation assay (RIPA) buffer, followed by ultracentrifugation and solubilization of RIPA insoluble proteins in urea buffer. The ultracentrifugation-cleared RIPA insoluble protein fraction is widely used to study protein insolubility in the context of neurodegeneration (Nuber et al., 2013; Walker et al., 2015). Label-free mass spectrometry of the insoluble protein fraction was utilized to identify proteins that are insoluble in sALS and fALS, relative to control iPSC-MNs (Figure 1A). Gene ontology (GO) analysis of the 100 proteins (top 2.9% of all detected proteins) with the highest label free quantification (LFQ) intensities in controls (Figure S1J) revealed that ‘unfolded protein binding’ (corrected P = 7.95 x 10-16) and ‘structural constituent of cytoskeleton’ (corrected P = 1.47 x 10-10) were among the 10 most significantly enriched GO terms, indicating enrichment of insoluble proteins (Figure S1K). Principle component analysis of the insoluble fractions did not distinguish ALS from control samples, suggesting that the overall insoluble proteome is not changed (Figure S1L). At threshold P ≤ 0.05 (Welch’s t-test) and fold change ≥ 1.5, we identified 88 proteins enriched in the insoluble fraction in ALS samples relative to control (Figure 1B). When the sample labels were randomly shuffled, we observed an average of 7.5 proteins (~12-fold lower) as differentially enriched at the same statistical thresholds, indicative of an ALS-specific protein insolubility pattern (Figure 1C). The 88 candidate proteins included cytoskeletal components and motor proteins, functional categories associated with prominent ALS in vitro phenotypes (Akiyama et al., 2019; Egawa et al., 2012; Fazal et al., 2021; Guo et al., 2017; Kreiter et al., 2018) (Figure 1D). Notably, 5 RBPs, NOVA1, ELAVL4, FXR2, RBFOX2, and RBFOX3 were also enriched (Figure 1D). The NOVA1 paralog NOVA2 was significantly enriched (P = 0.03) but did not meet our enrichment threshold (fold change = 1.36). Interestingly, insoluble TDP-43 protein was not significantly different in ALS and control (P = 0.98; fold change = 0.97). Western blot analysis confirmed the increase in insolubility of NOVA1, NOVA2, ELAVL4, RBFOX2 and RBFOX3 (Figure 1E and 1F). The soluble protein levels of NOVA1 and NOVA2 were also increased (Figure 1F). In conclusion, we identified 5 RBPs with elevated insoluble protein levels of ALS-iPSC-MNs.

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Transcriptome analysis of pancreatic cancer patients with low and high metabolic tumor volume (MTV)

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