Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics
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 bulk RNA-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.
Authors
- Arnav Mehta (ORCID: https://orcid.org/0000-0002-0313-2848)
- Itay Tirosh (ORCID: https://orcid.org/0000-0001-5477-2987)
- Genevieve Marie Boland (ORCID: https://orcid.org/0000-0002-7522-6173)
- Simon Mages (ORCID: https://orcid.org/0000-0003-1447-6811)
- Shinya Imada
- Inbal Avraham‐Davidi (ORCID: https://orcid.org/0000-0001-7118-9179)
- Danielle Dionne (ORCID: https://orcid.org/0000-0002-8338-4323)
- Matan Hofree (ORCID: https://orcid.org/0000-0001-8368-0299)
- Karin Pelka (ORCID: https://orcid.org/0000-0003-2856-8602)
- Nir Hacohen (ORCID: https://orcid.org/0000-0002-2349-2656)
- Mor Nitzan (ORCID: https://orcid.org/0000-0003-0074-9196)
- Noa Moriel
- Jana Laláková (ORCID: https://orcid.org/0000-0002-4190-1476)
- Toni Delorey (ORCID: https://orcid.org/0000-0001-6614-3803)
- Hao Xu (ORCID: https://orcid.org/0000-0002-2169-115X)
- Morgane Rouault
- Ralf Strasser
- Leah Caplan (ORCID: https://orcid.org/0000-0002-6594-1608)
- Aviv Regev
- Jatin Roper (ORCID: https://orcid.org/0000-0002-8851-1352)
- Johanna Klughammer (ORCID: https://orcid.org/0000-0002-3628-9278)
- Anezka Niesnerova (ORCID: https://orcid.org/0009-0001-9067-1494)
- Fei Chen (ORCID: https://orcid.org/0000-0003-2308-3649)
- Ömer Yılmaz (ORCID: https://orcid.org/0000-0002-0962-2725)
- Jonathan Chen (ORCID: https://orcid.org/0000-0001-6074-9302)
- Evan Murray (ORCID: https://orcid.org/0000-0002-9195-7478)
- Orit Rozenblatt‐Rosen
Institutions
- Broad Institute (US)
- Gladstone Institutes (US)
- Harvard University (US)
- Duke University (US)
- University of California, San Francisco (US)
- Hebrew University of Jerusalem (IL)
- Massachusetts General Hospital (US)
- Moscow Institute of Thermal Technology (RU)
- Universidad Católica de Santa Fe (AR)
- Marion General Hospital (US)
- Dana-Farber Cancer Institute (US)
- 10X Genomics (United States) (US)
- FZU ‒ Institute of Physics of the Academy of Sciences of the Czech Republic (CZ)
- Allen Institute (US)
- Harvard Stem Cell Institute (US)
- Congenomics (United States) (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Weizmann Institute of Science (IL)
- Massachusetts Institute of Technology (US)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- eLife
- Published
- 2025-03-11
- DOI
- https://doi.org/10.7554/elife.104815
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00