Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics
Cite
Avraham-Davidi, I., Mages, S., Klughammer, J., Moriel, N., Imada, S., Hofree, M., Murray, E., Chen, J., Pelka, K., Mehta, A. and Boland, G.M., 2025. Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics. eLife, 14. https://doi.org/10.7554/eLife.104815.1
Abstract
While advances in single cell genomics have helped to chart the cellular components of tumor ecosystems, it has been more challenging to characterize their specific spatial organization and functional interactions. Here, we combine single cell RNA-seq, spatial transcriptomics by Slide- seq, and in situ multiplex RNA analysis, to create a detailed spatial map of healthy and dysplastic colon cellular ecosystems and their association with disease progression. We profiled inducible genetic CRC mouse models that recapitulate key features of human CRC, assigned cell types and epithelial expression programs to spatial tissue locations in tumors, and computationally used them to identify the regional features spanning different cells in the same spatial niche. We find that tumors were organized in cellular neighborhoods, each with a distinct composition of cell subtypes, expression programs, and local cellular interactions. Comparing to scRNA-seq and Slide-seq data from human CRC, we find that both cell composition and layout features were conserved between the species, with mouse neighborhoods correlating with malignancy and clinical outcome in human patient tumors, highlighting the relevance of our findings to human disease. Our work offers a comprehensive framework that is applicable across various tissues, tumors, and disease conditions, with tools for the extrapolation of findings from experimental mouse models to human diseases.
Datasets
1. scRNA-seq data from healthy colon or dysplastic lesions
ExploreDate of birth
Date
Flow cell
Hashed
Hash index
Lane ID
Mouse model
Sample ID
State
Cell type (cluster)
Cell type (labels)
Cell type (compartment)
Cell type (cluster short)
Coarse state
Leiden clustering
Biosample ID
Subject ID
Sex
Cell type
Disease
Tissue
Assay
Mouse strain
Age
WT (+ injection)12,473 cells WT (AV w/o injection)5,039 cells malignant (3weeks)4,311 cells malignant (9weeks)3,056 cells Epi01 (Dysplastic Stem Like)15,743 cells Epi02 (Enterocytes)5,655 cells Epi03 (Stem/Progenitors)4,908 cells Epi04 (Secretory)3,646 cells Epi05 (Dysplastic Secretory Like)1,480 cells Mono02 (Dysplasia-Associated)1,239 cells Mono03 (Dysplasia-Associated, IFN)810 cells TNK02 (Th1/Th17)596 cells TNK05 (GdT_Il17+)410 cells Endo01 (Vascular)229 cells Endo02 (Lymphatic)211 cells Epi07 (Enteroendocrine)160 cells TNK08 (ProliferatingTC)151 cells Fibro02 (Myofibroblasts)43 cells TNK09 (CD4_Tgfb1+)36 cells malignant cell17,223 cells enterocyte of colon5,655 cells intestinal crypt stem cell of colon4,908 cells colon glandular cell3,646 cells colon epithelial cell1,068 cells regulatory T cell316 cells blood vessel endothelial cell229 cells endothelial cell of lymphatic vessel211 cells enteroendocrine cell of colon160 cells natural killer cell159 cells myofibroblast cell43 cells colorectal carcinoma30,605 cells 2. scRNA-seq data from healthy colon or dysplastic lesions - Epithelial programs
ExploreLeiden clustering
Date of birth
Date
Flow cell
Hash index
Mouse model
Sample ID
State
Cell type (cluster)
Cell type (labels)
Cell type (compartment)
Cell type (cluster short)
Coarse state
Subject ID
Sex
Cell type
Disease
Tissue
Assay
Mouse strain
Age
WT (+ injection)9,501 cells WT (AV w/o injection)3,802 cells malignant (3weeks)3,100 cells malignant (9weeks)1,365 cells Epi01 (Dysplastic Stem Like)15,743 cells Epi02 (Enterocytes)5,655 cells Epi03 (Stem/Progenitors)4,908 cells Epi04 (Secretory)3,646 cells Epi05 (Dysplastic Secretory Like)1,480 cells Epi07 (Enteroendocrine)160 cells malignant cell17,223 cells enterocyte of colon5,655 cells intestinal crypt stem cell of colon4,908 cells colon glandular cell3,646 cells colon epithelial cell1,068 cells enteroendocrine cell of colon160 cells colorectal carcinoma19,357 cells 3. Slide-Seq from mouse colons
ExploreTissue region
State
Sample ID
Epi domain
Leiden clustering
Biosample ID
Subject ID
Sex
Disease
Tissue
Assay
Age
Mouse strain
Region 2 (Muscularis)51,892 cells Region 10 (Normal)31,602 cells Region 1 (Stem cell niche - dysplastic)28,034 cells Region 3 (Normal)27,856 cells Region 8 (Malignant-like, Deep crypt-like)23,790 cells Region 5 (Stem cell niche - normal)23,181 cells Region 6 (Malignant-like, inflammation)21,453 cells Region 11 (Malignant-like, EMT)20,476 cells Region 12 (Normal)16,761 cells premalignant231,471 cells colorectal carcinoma231,471 cells 4. Multiplex in situ RNA profiles with the Cartana
ExploreSample ID
State
Assay version
Subject ID
Sex
Disease
Tissue
Assay
Mouse strain
Age
Leiden clustering
premalignant418,153 cells colorectal carcinoma418,153 cells Alias names
GSE260801, GSE260797, GSE260798, GSE260799, GSE260800, SCP1891
