Metallomics Reviews
Spatial Metallomics in Colorectal Cancer: Metals-Pathway Map
What was reviewed and who was studied
Original proof-of-concept study integrating elemental imaging with spatial transcriptomics in a single human colorectal cancer (CRC) case. The subject was a 55–60-year-old female with a left-colon, microsatellite-stable primary tumor and liver metastasis; one FFPE tumor section was analyzed with adjacent serial sections. Primary matrix: FFPE tumor tissue (with tumor core, tumor–interface, muscularis propria, serosa annotated); no secondary biofluids. Laser ablation ICP-TOF-MS (LA-ICP-TOF-MS) provided 5-μm elemental maps; 10x Visium CytAssist profiled spatial transcriptomes (∼18,000 genes; 55-μm spots) with single-cell RNA-seq from a serial section for cell-type deconvolution. Spatial co-registration used TRACE; analysis included Getis-Ord Gi* hotspot statistics, Cell2Location, Spearman correlations, Enrichr pathway analysis, MEFISTO factorization, and MISTy spatial modeling. Design: observational, cross-sectional.
Major Findings
Copper (Cu), magnesium (Mg), iron (Fe), and manganese (Mn) were enriched intratumorally; zinc (Zn), potassium (K), and calcium (Ca) were highest at the tumor–interface/muscularis. Cu hotspots colocalized with immune and endothelial compartments, while Fe associated with a mesenchymal/stromal phenotype and the tumor’s proliferative front
| Metal(s) | Spatial enrichment & pathway associations (adjusted p) |
|---|
| Cu, Mg, Fe, Mn | Enriched intratumorally; Cu hotspots co-localize with immune/endothelial niches. |
| Zn, K, Ca | Highest at tumor–interface/muscularis. |
| Cu | Interferon-γ response (1.09×10⁻¹²); G2–M checkpoint (1.30×10⁻⁷). |
| Fe | EMT (4.38×10⁻²¹); hypoxia (8.81×10⁻⁴); angiogenesis (1.04×10⁻²); KRAS signaling up (1.60×10⁻¹⁶); aligned with mesenchymal/stromal phenotype and proliferative front. |
| Zn, K | Myogenesis and smooth-muscle programs (p ≤ 1.69×10⁻¹⁷). |
Implications for Microbial Metallomics
The metallome’s spatial heterogeneity tracked immune activation, stromal remodeling, and epithelial–mesenchymal transitions, indicating that metal availability and transporters shape tumor-microenvironment physiology in situ.
| Concept | Implication |
|---|---|
| Cu hotspots with interferon/JAK–STAT signatures | Metal-linked nutrient immunity readouts in immune niches |
| Cu–ATOX1/ATP7A with SOD3 downregulation | Transporter–chaperone axis tied to extracellular redox and immune tone |
| Fe with EMT genes (FN1, SPARC, MMP9) | Iron-rich stromal fronts as invasion/remodeling micro-domains |
| Zn/K with myogenesis/smooth-muscle signaling | Interface metallome reflects muscularis programs relevant to barrier function |
| Mn with dendritic cells and PD-1 pathways | Mn-linked antigen-presenting cell niches and checkpoint context |
| Predictive spatial models (R² >75%) | Joint metallome–transcriptome features can serve as spatial diagnostics |
Limitations
Single-patient, single-timepoint analysis limits generalizability and causal inference. FFPE preparation and paraffin retention can attenuate/redistribute elements; LA-ICP-TOF-MS cannot assign oxidation state/speciation.Absolute concentrations were not reported; analyses relied on Gi* z-scores.
Key takeaways for Researchers and Clinicians
This single-case CRC study integrated LA-ICP-TOF-MS with Visium and single-cell deconvolution on FFPE sections using TRACE. Cu, Fe, Zn, Mg, Mn, Ca, and K showed distinct spatial programs, with Cu linked to interferon/G2–M pathways and Fe to EMT/hypoxia/angiogenesis. Gene-level correlations highlighted Cu transport/chaperone networks and Fe-associated ECM remodeling; spatial models explained >75% of variance for multiple elements. Methodologically, Gi* hotspotting plus spatial modeling provided interpretable, tissue-contextual features. Spatial metallome–transcriptome integration is poised to yield diagnostic and therapeutic biomarkers at immune and invasive fronts.
Citation
Srivastava A, Shaik N, Lu Y, et al. Integration of elemental imaging and spatial transcriptomic profiling for proof-of-concept metals-based pathway analysis of colon tumor microenvironment. Metallomics. 2025;17:mfaf034. doi:10.1093/mtomcs/mfaf034