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Multiplexed 3D atlas of state transitions and immune interactions in colorectal cancer

View ORCID ProfileJia-Ren Lin, View ORCID ProfileShu Wang, View ORCID ProfileShannon Coy, View ORCID ProfileMadison Tyler, View ORCID ProfileClarence Yapp, View ORCID ProfileYu-An Chen, View ORCID ProfileCody N. Heiser, View ORCID ProfileKen S. Lau, View ORCID ProfileSandro Santagata, View ORCID ProfilePeter K. Sorger
doi: https://doi.org/10.1101/2021.03.31.437984
Jia-Ren Lin
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
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Shu Wang
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
3Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, 02138, USA
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Shannon Coy
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Madison Tyler
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
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Clarence Yapp
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
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Yu-An Chen
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
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Cody N. Heiser
1Human Tumor Atlas Network
5Program in Chemical & Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
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Ken S. Lau
1Human Tumor Atlas Network
6Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
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Sandro Santagata
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Peter K. Sorger
1Human Tumor Atlas Network
2Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
7Department of Systems Biology, Harvard Medical School, Boston, MA, 02115, USA
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  • For correspondence: peter_sorger@hms.harvard.edu
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SUMMARY

Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells that invade adjacent tissue and spread to distant sites. Here we use highly multiplexed tissue imaging, spatial statistics, and machine learning to identify cell types and states underlying morphological features of known diagnostic and prognostic significance in colorectal cancer. We find that a thorough spatial analysis requires imaging the entire tumor region, not small fields of view (e.g. those found in tissue microarrays). When this condition is met, the data reveal frequent transitions between histological archetypes (tumor grades and morphologies) correlated with molecular gradients. At the tumor invasive margin, where tumor, normal, and immune cells compete, localized features in 2D such as tumor buds and mucin pools are seen in 3D to be large connected structures having continuously varying molecular properties. Immunosuppressive cell-cell interactions also exhibit graded variation in type and frequency. Thus, whereas scRNA-Seq emphasizes discrete changes in tumor state, whole-specimen imaging reveals the presence of large- and small-scale spatial gradients analogous to those in developing tissues.

Competing Interest Statement

PKS is a member of the SAB or BOD member of Applied Biomath, RareCyte Inc., and Glencoe Software, which distributes a commercial version of the OMERO database; PKS is also a member of the NanoString SAB. In the last five years the Sorger lab has received research funding from Novartis and Merck. Sorger declares that none of these relationships have influenced the content of this manuscript. SS is a consultant for RareCyte Inc.

Footnotes

  • https://www.cycif.org/data/Lin-Wang-Coy-Sorger-HTAN-2021

  • https://www.cycif.org/crc1-intro

  • https://www.cycif.org/crc1-3d

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 02, 2021.
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Multiplexed 3D atlas of state transitions and immune interactions in colorectal cancer
Jia-Ren Lin, Shu Wang, Shannon Coy, Madison Tyler, Clarence Yapp, Yu-An Chen, Cody N. Heiser, Ken S. Lau, Sandro Santagata, Peter K. Sorger
bioRxiv 2021.03.31.437984; doi: https://doi.org/10.1101/2021.03.31.437984
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Multiplexed 3D atlas of state transitions and immune interactions in colorectal cancer
Jia-Ren Lin, Shu Wang, Shannon Coy, Madison Tyler, Clarence Yapp, Yu-An Chen, Cody N. Heiser, Ken S. Lau, Sandro Santagata, Peter K. Sorger
bioRxiv 2021.03.31.437984; doi: https://doi.org/10.1101/2021.03.31.437984

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