# SC2Spa: a deep learning based approach to map transcriptome to spatial origins at cellular resolution

**Authors:** Linbu Liao, Esha Madan, António M. Palma, Hyobin Kim, Amit Kumar, Praveen Bhoopathi, Robert Winn, Jose Trevino, Paul Fisher, Cord Herbert Brakebusch, Gahyun Kim, Junil Kim, Rajan Gogna, Kyoung Jae Won

PMC · DOI: 10.1186/s12859-025-06173-6 · BMC Bioinformatics · 2025-06-02

## TL;DR

SC2Spa is a deep learning method that accurately maps cells to their spatial locations in tissues using transcriptomic data, improving understanding of cellular organization.

## Contribution

SC2Spa introduces a novel deep learning approach that outperforms existing methods in mapping transcriptomes to spatial origins and identifying spatially variable genes.

## Key findings

- SC2Spa outperformed other predictors in mapping single cell RNA sequencing data to spatial coordinates.
- The method is robust across various spatial transcriptomics technologies and resolutions.
- SC2Spa can identify spatially variable genes not detectable with previous approaches.

## Abstract

Understanding cellular heterogeneity within tissues hinges on knowledge of their spatial context. However, it is still challenging to accurately map cells to their spatial coordinates.

We present SC2Spa, a deep learning-based approach that learns intricate spatial relationships from spatial transcriptomics (ST) data. Benchmarking tests show that SC2Spa outperformed other predictors and accurately detected tissue architecture from transcriptome. SC2Spa successfully mapped single cell RNA sequencing (scRNA-seq) to Visium assay, providing an approach to enhance the resolution for low resolution ST data. Our test showed that SC2Spa performs well for various ST technologies and robust to spatial resolution. In addition, SC2Spa can suggest spatially variable genes that cannot be identified from previous approaches.

SC2Spa is a robust and accurate approach to provide single cells with their spatial location and identify spatially meaningful genes.

The online version contains supplementary material available at 10.1186/s12859-025-06173-6.

## Full-text entities

- **Genes:** Csta2 (cystatin A family member 2) [NCBI Gene 76770] {aka 2010005H15Rik}, Gm19684 (predicted gene, 19684) [NCBI Gene 100503422], Krt75 (keratin 75) [NCBI Gene 109052] {aka 4732468K03Rik, K6hf, Krt2-6hf, Krtcap1}, Ttr (transthyretin) [NCBI Gene 22139] {aka prealbumin}, Hbegf (heparin-binding EGF-like growth factor) [NCBI Gene 15200] {aka Dtr, Dts, Hegfl}, FASN (fatty acid synthase) [NCBI Gene 2194] {aka FAS, OA-519, SDR27X1}, Hs3st4 (heparan sulfate (glucosamine) 3-O-sulfotransferase 4) [NCBI Gene 628779] {aka Gm6915}, MT1H (metallothionein 1H) [NCBI Gene 4496] {aka MT-0, MT-1H, MT-IH, MT1}, Calb2 (calbindin 2) [NCBI Gene 12308] {aka CR}, Otof (otoferlin) [NCBI Gene 83762], Stard8 (StAR related lipid transfer domain containing 8) [NCBI Gene 236920] {aka Dlc3, mKIAA0189}, Eps8l2 (EPS8-like 2) [NCBI Gene 98845] {aka Eps8r2}, CYB561 (cytochrome b561) [NCBI Gene 1534] {aka CGCytb, CYB561A1, FRRS2, ORTHYP2}, Tmem171 (transmembrane protein 171) [NCBI Gene 380863] {aka Gm905}, Erbb4 (erb-b2 receptor tyrosine kinase 4) [NCBI Gene 13869] {aka Her4, c-erbB-4}, Has1 (hyaluronan synthase 1) [NCBI Gene 15116] {aka HAS}, Fibcd1 (fibrinogen C domain containing 1) [NCBI Gene 98970], DMKN (dermokine) [NCBI Gene 93099] {aka UNQ729, ZD52F10}, Mbp (myelin basic protein) [NCBI Gene 17196] {aka Hmbpr, golli-mbp, jve, mld, shi}, Phex (phosphate regulating endopeptidase homolog, X-linked) [NCBI Gene 18675] {aka Gy, HPDR, HPDR1, Hyp, PEX}, Rgs9 (regulator of G-protein signaling 9) [NCBI Gene 19739] {aka RGS9-1, Rgs9-2}, Slc17a6 (solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6) [NCBI Gene 140919] {aka 2900073D12Rik, DNPI, VGLUT2}, RPL37 (ribosomal protein L37) [NCBI Gene 6167] {aka L37, eL37}, Tert (telomerase reverse transcriptase) [NCBI Gene 21752] {aka EST2, TCS1, TP2, TR, TRT}, Tshz2 (teashirt zinc finger family member 2) [NCBI Gene 228911] {aka 2900073F20Rik, B830045G17, Mtsh2, Sdccag33l, Tsh2, Zfp218}, RASD1 (ras related dexamethasone induced 1) [NCBI Gene 51655] {aka AGS1, DEXRAS1, MGC:26290}, Gm10640 (predicted gene 10640) [NCBI Gene 100038516] {aka EG668322}, Gm13872 [NCBI Gene 100379604], EGR1 (early growth response 1) [NCBI Gene 1958] {aka AT225, G0S30, KROX-24, NGFI-A, TIS8, ZIF-268}, KCNJ1 (potassium inwardly rectifying channel subfamily J member 1) [NCBI Gene 3758] {aka KIR1.1, ROMK, ROMK1}, PVALB (parvalbumin) [NCBI Gene 5816] {aka D22S749}, Nrgn (neurogranin) [NCBI Gene 64011] {aka 0710001B06Rik, NG, NG/RC3, Pss1, RC3}, Car3 (carbonic anhydrase 3) [NCBI Gene 12350] {aka Ca3, Car-3}, Hpca (hippocalcin) [NCBI Gene 15444], Pcp4 (Purkinje cell protein 4) [NCBI Gene 18546] {aka P16Rimb19, Pcp-4, Pep19}
- **Diseases:** CDF (MESH:D012090), ReLU (MESH:D017499), breast cancer (MESH:D001943), RAM (MESH:D008569), kidney cancer (MESH:D007680), DPCs (MESH:D002527)
- **Chemicals:** formalin (MESH:D005557), ST (-), paraffin (MESH:D010232), Si (MESH:D012825)
- **Species:** Homo sapiens (human, species) [taxon 9606], Mus musculus (house mouse, species) [taxon 10090], Drosophila melanogaster (fruit fly, species) [taxon 7227]
- **Cell lines:** MTAB-11115 — Homo sapiens (Human), Trisomy 9, Finite cell line (CVCL_5P40), MERFISH — Homo sapiens (Human), Osteosarcoma, Cancer cell line (CVCL_YK69), MTAB-11114 — Homo sapiens (Human), Transformed cell line (CVCL_GE91)

## Full text

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## Figures

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## References

8 references — full list in the complete paper: https://tomesphere.com/paper/PMC12131412/full.md

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Source: https://tomesphere.com/paper/PMC12131412