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Transfer Learning Reveals Cancer-Associated Fibroblasts Are Associated with Epithelial-Mesenchymal Transition and Inflammation in Cancer Cells in Pancreatic Ductal Adenocarcinoma.
UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by an immunosuppressive tumor microenvironment enriched with cancer-associated fibroblasts (CAF). This study used a convergence approach to identify tumor cell and CAF interactions through the integration of single-cell data from human tumors with human organoid coculture experiments. Analysis of a comprehensive atlas of PDAC single-cell RNA sequencing data indicated that CAF density is associated with increased inflammation and epithelial-mesenchymal transition (EMT) in epithelial cells. Transfer learning using transcriptional data from patient-derived organoid and CAF cocultures provided in silico validation of CAF induction of inflammatory and EMT epithelial cell states. Further experimental validation in cocultures demonstrated integrin beta 1 (ITGB1) and vascular endothelial factor A (VEGFA) interactions with neuropilin-1 mediating CAF-epithelial cell cross-talk. Together, this study introduces transfer learning from human single-cell data to organoid coculture analyses for experimental validation of discoveries of cell-cell cross-talk and identifies fibroblast-mediated regulation of EMT and inflammation. SIGNIFICANCE: Adaptation of transfer learning to relate human single-cell RNA sequencing data to organoid-CAF cocultures facilitates discovery of human pancreatic cancer intercellular interactions and uncovers cross-talk between CAFs and tumor cells through VEGFA and ITGB1.
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A human-mouse atlas of intrarenal myeloid cells identifies conserved disease-associated macrophages in lupus nephritis.
Monocytes and macrophages in patients with lupus nephritis exhibit altered behavior compared with healthy kidneys. How to optimally use mouse models to develop treatments targeting these cells is poorly understood. This study compared intrarenal myeloid cells in four mouse models and 155 lupus nephritis patients using single-cell profiling, spatial transcriptomics, and functional studies. Across mouse models, monocyte and macrophage subsets consistently expanded or contracted in disease. A subset of murine classical monocytes expanded in disease; these cells expressed Cd9, Spp1, Ctsd, Cd63, Apoe, and Trem2, genes associated with tissue injury in other organs that play roles in inflammation, lipid metabolism, and tissue repair. Resident macrophages expressed similar genes in clinical disease. In humans, we identified analogous disease-associated monocytes and macrophages that were associated with kidney histological subtypes and disease progression, sharing gene expression and localizing to similar kidney microenvironments as in mice. This cross-species analysis supports the use of mouse functional studies for understanding human lupus nephritis.
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MITI minimum information guidelines for highly multiplexed tissue images.
The imminent release of tissue atlases combining multi-channel microscopy with single cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards that guide data deposition, curation and release. We describe a Minimum Information about highly multiplexed Tissue Imaging (MITI) standard that applies best practices developed for genomics and other microscopy data to highly multiplexed tissue images and traditional histology.
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A comprehensive spatial proteome landscape of ectopic lymphoid-like structures in metastatic colorectal cancer reveals specific signatures for predicting clinical outcomes.
We previously generated a global bulk-level proteogenomic atlas of metastatic colorectal cancer (CRC) in a Chinese cohort (CCRC). Using formalin-fixed paraffin-embedded tissues from this cohort, we identified 2095 ectopic lymphoid-like structures (ELSs) across 132 primary tumors. Both lymphoid aggregates (Aggs) and tertiary lymphoid structures (TLSs) were significantly associated with metastasis and clinical outcomes in CRC, in which the spatial and compositional heterogeneity of ELSs and their clinical relevance remain unknown. Here, we upgraded our LCM-MTA platform to version 2.0 for deep spatial proteomics and profiled spatial proteomic landscapes from matched mCRC and non-mCRC cases with comparable baseline clinical features. This analysis revealed pronounced spatial heterogeneity in protein expression, distinguishing ELSs from parenchymal regions in paired tumor and para-carcinoma tissues. Notably, TLSs displayed distinct functional states: mCRC-associated TLSs showed enrichment of anti-tumor immune activation pathways, whereas non-mCRC TLSs were enriched in acute inflammatory response pathways. Based on these findings, we developed a 13-protein TLS signature and scoring system to predict metastasis and prognosis in the CCRC cohort, validated in two independent CPTAC cohorts. We present a comprehensive spatial proteomic map of ELSs in metastatic CRC and identify a TLS-based signature with strong potential for predicting metastasis and clinical outcomes.
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A hybrid epithelial/mesenchymal state in head and neck cancer: A biomarker for survival with differential prognosis by self-reported race.
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the 6th leading cause of cancer-related mortality, with racial disparities amplifying the challenges in treatment. Although the relationship between hybrid epithelial/mesenchymal (E/M) states and tumor progression is of interest, no studies have characterized the clinical relevance of hybrid E/M states in head and neck cancer outcomes among self-reported racial cohorts. METHODS: Given the overlap in gene expression between hybrid E/M malignant cells and cancer-associated fibroblasts, we utilized deconvolution of bulk RNA sequencing data from oral cavity and laryngeal squamous cell carcinoma tumors from The Cancer Genome Atlas. We utilized our previously collected single-cell profiles to generate inferred malignant profiles and then scored these for hybrid E/M. We then conducted a survival analysis on overall and disease-free survival among self-reported Black and White Americans. FINDINGS: The hybrid E/M state was differentially associated with head and neck cancer survival by self-reported race and ethnicity, with a stronger association in non-Hispanic Black patients. Black patients with a high hybrid E/M score had a higher risk of death or recurrence (hazard ratio [HR]: 4.18 [95% confidence interval (CI): 2.06, 8.49]) than White patients with a high hybrid E/M score (HR: 1.58 [95% CI: 1.11, 2.26]). CONCLUSION: Our results suggest a complex interplay of social structure, racism, and genetic diversity. We implore researchers to consider the social and biological context contributing to disparities. FUNDING: A.L.M. received support from the National Institute of Minority Health and Health Disparities (K01MD013897 [principal investigator (PI), A.L.M.]). S.V.P. received support from the National Institute of Dental and Craniofacial Research (R01DE032865 [PI, S.V.P.] and R01DE032371 [PI, S.V.P.]).
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The Andrographolide Analogue 3A.1 Synergizes with Taxane Derivatives in Aggressive Metastatic Prostate Cancers by Upregulation of Heat Shock Proteins and Downregulation of MAT2A-Mediated Cell Migration and Invasion.
Conventional treatment with taxanes (docetaxel-DTX or cabazitaxel-CBZ) increases the survival rates of patients with aggressive metastatic castration-resistant prostate cancer (mCRPC); however, most patients acquire resistance to taxanes. The andrographolide analog, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1), has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX/CBZ against mCRPC and their mechanism of action. Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. Chou-Talalay's combination index (CI) values of all 3A.1 + TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX and CBZ (P < 0.05). Caspase assay (apoptosis) results concurred with in vitro cytotoxicity data. RNA sequencing (RNAseq), followed by ingenuity pathway analysis (IPA), identified that upregulation of heat-shock proteins (Hsp70, Hsp40, Hsp27, and Hsp90) and downregulation of MAT2A as the key player for 3A.1 response. Furthermore, the top treatment-induced differentially expressed genes (DEGs) belong to DNA damage, cell migration, hypoxia, autophagy (MMP1, MMP9, HIF-1α, Bag-3, H2AX, HMOX1, PSRC1), and cancer progression pathways. Most importantly, top downregulated DEG MAT2A has earlier been shown to be involved in cell migration and invasion. Furthermore, using in silico analysis on the Cancer Genome Atlas (TCGA) database, this study found that MAT2A and highly co-expressed (r > 0.7) genes, TRA2B and SF1, were associated with worse Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). Immunoblotting, comet, and migration assays corroborated these findings. These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive PCa. SIGNIFICANCE STATEMENT: The andrographolide analogue, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1), showed anticancer activity against metastatic castration-resistant and neuroendocrine variant prostate cancers (mCRPC/NEPC). Additionally, 3A.1 exhibited synergistic anticancer effect in combination with standard chemotherapy drugs docetaxel and cabazitaxel in mCRPC/NEPC. Post-treatment gene expression studies revealed that heat shock proteins (Hsp70, Hsp40, Hsp27, and Hsp90) and MAT2A are important in the mechanism of 3A.1 action and drug response. Furthermore, DNA damage, cell migration, hypoxia, and autophagy were crucial pathways for the anticancer activity of 3A.1.
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Spatially organized multicellular immune hubs in human colorectal cancer.
Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.
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Spatiotemporal modeling of molecular holograms.
Quantifying spatiotemporal dynamics during embryogenesis is crucial for understanding congenital diseases. We developed Spateo (https://github.com/aristoteleo/spateo-release), a 3D spatiotemporal modeling framework, and applied it to a 3D mouse embryogenesis atlas at E9.5 and E11.5, capturing eight million cells. Spateo enables scalable, partial, non-rigid alignment, multi-slice refinement, and mesh correction to create molecular holograms of whole embryos. It introduces digitization methods to uncover multi-level biology from subcellular to whole organ, identifying expression gradients along orthogonal axes of emergent 3D structures, e.g., secondary organizers such as midbrain-hindbrain boundary (MHB). Spateo further jointly models intercellular and intracellular interaction to dissect signaling landscapes in 3D structures, including the zona limitans intrathalamica (ZLI). Lastly, Spateo introduces "morphometric vector fields" of cell migration and integrates spatial differential geometry to unveil molecular programs underlying asymmetrical murine heart organogenesis and others, bridging macroscopic changes with molecular dynamics. Thus, Spateo enables the study of organ ecology at a molecular level in 3D space over time.
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Blockage of EGFR/AKT and mevalonate pathways synergize the antitumor effect of temozolomide by reprogramming energy metabolism in glioblastoma.
BACKGROUND: Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR-vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation. METHODS: Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo. RESULTS: GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models. CONCLUSIONS: Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.