Christopher Cherry

Supplemental Table 2: Pattern 1 Pathways from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

Supplemental Table 1: Pancreas Gene Markers from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

Supplemental Table 3: Pattern 7 Ordered Genes from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

Supplementary methods and figures

BACKGROUND: Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide, endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). We hypothesized that distinct and overlapping gene expression patterns in SSc-PAH versus IPAH lung tissues could inform the investigation of precision-targeted therapies. METHODS: Lung tissue samples from 4 SSc-PAH, 4 IPAH, and 4 failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative lung tissue bank. Single-cell RNA sequencing was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis, transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map. RESULTS: SSc-PAH samples showed a higher proportion of fibroblasts compared with failed donors and a higher proportion of dendritic cells/macrophages compared with IPAH. Gene set enrichment analysis revealed enriched pathways related to epithelial-to-mesenchymal transition, apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial-to-endothelial cell signaling observed. Macrophage-to-endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures. CONCLUSIONS: Overlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve outcomes in patient with SSc-PAH. Future studies should validate these targets and explore their therapeutic efficacy.

Here we investigate why the effects of increasing FOXM1 activity in β-cells observed in male mice are not seen in female mice. ERα likely collaborates with FOXM1 and other transcription factors to enhance gene expression related to β-cell function. Higher estrogen levels in females may contribute to their increased insulin secretion and the more severe consequences of losing transcription factors like FOXM1 in males. Overall, these findings shed light on sex differences in diabetes susceptibility.

The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase–wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.

Supplemental Table 1: Pancreas Gene Markers from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

Supplemental Table 3: Pattern 7 Ordered Genes from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma

Supplemental Table 1: Pancreas Gene Markers from Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial–Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma