Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.03.18.712664

Mapping spatial cell-cell communication programs by tailoring chains of cells for transformer neural networks

Brunn, N.·Guitart, L. C.·Farhadyar, K.·Fullio, C. L.·Kailer, J.·Vogel, T.·Hackenberg, M.·Binder, H.
View original source ↗Export metadata ↓

Abstract

Recent advances in spatial transcriptomics and computational modeling enable the study of cellular interactions in situ. However, existing methods quantify ligand-receptor activity pairwise or between predefined cell groups, yielding overlapping signals and limited ability to summarize concurrent interactions into programs while localizing communication hotspots. We introduce scCChain, a transformer-based framework that integrates ligand-receptor activity into spatially resolved communication programs and localizes hotspots at spot and single-cell resolution. scCChain first derives candidate programs using structured dimensionality reduction. Subsequently, it samples programspecific communication chains by linking transcriptionally similar sender cells to candidate receivers via weighted random walks on a distance-informed cell graph, borrowing signal from similar neighbors. Transformer-based modeling then scores chains to prioritize communication programs and pinpoint hotspots across the tissue. Applied to human breast cancer spatial transcriptomics data at spot and single-cell resolution, scCChain supports both exploratory communication program discovery and targeted analysis of user-specified ligand-receptor pairs. In spot-level data, it prioritizes a tumor-associated program enriched for pro-angiogenic signaling that localizes to invasive regions. In imaging-based data, it highlights CXCL12-CXCR4 communication hotspots at cellular resolution. Here, we demonstrate that chain-based transformer modeling enables interpretable discovery and mapping of biological meaningful spatial communication programs within complex tissues.

Explore related subjects

bioinformaticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Brunn, N., Guitart, L. C., Farhadyar, K., Fullio, C. L., Kailer, J., Vogel, T., Hackenberg, M., Binder, H.. 2026-03-20. Mapping spatial cell-cell communication programs by tailoring chains of cells for transformer neural networks. https://doi.org/10.64898/2026.03.18.712664

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Accounting for pseudo-replication of Linkage Disequilibrium for contemporary Ne estimation

The Linkage Disequilibrium (LD) of unlinked loci can be used to estimate contemporary effective population size (Ne) of one to a few generations ago. In genomic datasets loci on different chromosomes are considered unlinked, but there are many more pairs of unlinked loci than there are independent pairs of chromosomes, resulting to confidence intervals (C.I.) being too narrow if the non-independence is not taken into account. Simulations were run to investigate the correlation structure among LD of unlinked loci, which can be expressed by the LD of loci along the same chromosomes, based on a discovery of a novel Random Probe LD estimator. We classify the correlation into two categories: overlapping of loci and disjoint pairs. The former is induced from the same locus being considered twice and is the stronger form of correlation. These correlations feed into {rho}, a parameter to quantify the degree of pseudo-replication in a dataset, and further a correction formula from which C.I. can be properly inferred. We demonstrate the use of our method via an analysis of genomic data from the malaria-transmitting Anopheles gambiae s.s mosquitoes. Apart from the point and C.I. estimates, we find that Var((r^2 ) ) is inflated by about 550 times due to pseudo-replication, highlighting the danger of not handling genetic correlation properly.

bioinformatics↗
bioRxiv2026

Accurate and scalable decontamination of imaging-based spatial transcriptomics via optimal transport

Imaging-based spatial transcriptomics enables molecule-resolved profiling of gene expression and tissue organization in situ. However, segmentation errors, transcript spillover and three-dimensional cell overlap can introduce misassigned transcripts into cell-level expression profiles, compromising biological interpretation and obscuring genuine signals. Existing methods either remove suspect expression at the cost of signal loss or lack a biologically grounded criterion for transcript assignment. Here we present CellDot, an optimal-transport framework that determines the fate of each transcript by retaining it in its host cell, reassigning it to a plausible neighboring cell or removing it as background. By integrating reference-guided expression compatibility with spatial information and data-adaptive constraints, CellDot enables accurate and traceable molecule-level correction while preserving biologically meaningful variation. In evaluations across multiple human tumor datasets, CellDot exhibited superior performance compared to existing decontamination methods, successfully restoring spatial expression patterns that matched independent cross-platform measurements. Moreover, it significantly enhanced the recovery of cellular states, intercellular communication, and spatial niche programs. Our experiments using real data demonstrated CellDot's scalability and established it as the only method applicable to a whole-transcriptome Atera dataset, underscoring its distinct advantages in the field of spatial transcriptomics.

bioinformatics↗
bioRxiv2026

Interpretable Machine Learning Reveals Complementary Age-Related Signatures in the Oral and Gut Microbiome

Whether combining microbiome data from multiple body sites improves prediction, and whether different sites carry complementary or redundant information, are distinct questions that most studies conflate into a single accuracy metric. This work makes two contributions, one methodological and one biological, using paired stool and oral cavity microbiome samples from 44 subjects across two age groups, healthy adults and newborns (Ferretti et al., 2018). Methodologically, we show that a subject-matched fusion design combined with SHAP-based (SHapley Additive exPlanations) site attribution can detect complementary information between body sites even when no measurable accuracy gain results. This is a pattern that conventional model comparison would misread as a null result. Gut (stool) composition alone achieved near-perfect classification (area under the receiver operating characteristic curve, AUC = 1.00), and combined stool-oral models never exceeded this ceiling. A null baseline, bootstrap confidence intervals, and preprocessing sensitivity checks confirmed that this ceiling reflects genuine biological signal rather than an artifact. Despite the flat accuracy curve, SHAP analysis of the fused model showed that oral cavity features carried more total feature importance than stool features (58.1% versus 41.9%), indicating that the model draws on real, non-redundant information from both sites. Biologically, the taxa driving this pattern include Malassezia restricta, Staphylococcus epidermidis, and Prevotella melaninogenica. These taxa behave in a manner consistent with their established roles as early colonizers of the neonatal gut, skin, and oral cavity, once their model-specific behavior is verified directly against abundance data rather than inferred from the literature alone. An independent, substantially larger paired-cohort study using a different analytical method reports a compatible pattern. Together, these results support a model of oral-gut microbiome maturation as two distinct, complementary processes, and demonstrate that detecting this kind of relationship requires examining a model's internal reasoning rather than its accuracy alone.

bioinformatics↗