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

Jia-Ren Lin, Shu Wang, Shannon Coy, Yu-An Chen, Clarence Yapp, Madison Tyler, Maulik K. Nariya, Cody N. Heiser, Ken S. Lau, Sandro Santagata, and Peter K. Sorger

Cell, 186, 1-19, DOI: 10.1016/j.cell.2022.12.028

Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells characterized by high intratumoral variation. We use highly multiplexed tissue imaging, 3D reconstruction, spatial statistics, and machine learning to identify cell types and states underlying morphological features of known diagnostic and prognostic significance in colorectal cancer. Quantitation of these features in high-plex marker space reveals recurrent transitions from one tumor morphology to the next, some of which are coincident with long-range gradients in the expression of oncogenes and epigenetic regulators. At the tumor invasive margin, where tumor, normal, and immune cells compete, T-cell suppression involves multiple cell types and 3D imaging shows that seemingly localized 2D features such as tertiary lymphoid structures are commonly interconnected and have graded molecular properties. Thus, while cancer genetics emphasizes the importance of discrete changes in tumor state, whole-specimen imaging reveals large-scale morphological and molecular gradients analogous to those in developing tissues.

Publication | bioRxiv

Key Findings:

  • Multiplexed analysis shows intermixed tumor morphologies and molecular gradients

  • Various cancer characteristic cellular features are large, interconnected structures

  • 3D tertiary lymphoid structure (TLS) networks show intra-TLS patterning variation

  • PD1-PDL1 interactions are primarily between T and myeloid cells in this CRC cohort

Figure overview of the Colorectal Cancer Atlas dataset: The colorectal cancer atlas contains detailed 3D analysis of one CRC tissue specimen with CyCIF, H&E, and spatial transcriptomics, whole slide imaging of 16 additional tumor samples, and tissue microarray analysis of 92 tumors.

Colorectal Cancer Atlas

The CRC Atlas dataset contains images and other data being used for construction of an atlas of human colorectal cancer under the auspices of the Human Tumor Atlas Network. Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells that invade adjacent tissue and spread to distant sites. 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. This includes the tumor invasive margin, where tumor, normal, and immune cells compete and were diverse immunosuppressive environments are found.

Contents

Data Explorations

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Multiplexed 3D atlas of state transitions and immune interactions in colorectal cancer (CRC01 Z-stack)
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Multiplexed 3D atlas of state transitions and immune interactions in colorectal cancer (Graphical Abstract)
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CRC01 - introduction - Lin, Wang, Coy et al., 2021

Data Overviews

NOTE! These Data Overviews provide access to minimally processed Level 2 images with no annotation or quality control. Click any of the following thumbnail images for an interactive view of the full-resolution images.

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CRC01 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC01 - overview - Lin, Wang, Coy et al., 2021
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CRC02 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC02 - overview - Lin, Wang, Coy et al., 2021
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CRC03 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC03 - overview - Lin, Wang, Coy et al., 2021
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CRC04 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC04 - overview - Lin, Wang, Coy et al., 2021
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CRC05 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC05 - overview - Lin, Wang, Coy et al., 2021
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CRC06 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC06 - overview - Lin, Wang, Coy et al., 2021
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CRC07 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC07 - overview - Lin, Wang, Coy et al., 2021
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CRC08 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC08 - overview - Lin, Wang, Coy et al., 2021
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CRC09 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC09 - overview - Lin, Wang, Coy et al., 2021
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CRC10 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC10 - overview - Lin, Wang, Coy et al., 2021
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CRC11 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC11 - overview - Lin, Wang, Coy et al., 2021
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CRC12 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC12 - overview - Lin, Wang, Coy et al., 2021
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CRC13 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC13 - overview - Lin, Wang, Coy et al., 2021
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CRC14 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC14 - overview - Lin, Wang, Coy et al., 2021
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CRC15 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC15 - overview - Lin, Wang, Coy et al., 2021
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CRC16 - H&E - overview - Lin, Wang, Coy et al., 2021
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CRC16 - overview - Lin, Wang, Coy et al., 2021
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CRC17 - H&E - overview - Lin, Wang, Coy et al., 2021

Code

All software used in this manuscript is freely available via GitHub at https://github.com/labsyspharm/mcmicro and https://github.com/labsyspharm/CRC_atlas_2022.

Access the Data

All data is available through a public repository (where available) or through AWS download. You should visit https://doi.org/10.5281/zenodo.7554924 to view the complete data table with information about where to find each dataset.

Funding Sources

This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors. This work was supported by NIH grants U54-CA225088 (PKS, SS), U2C-CA233280 (PKS, SS), U2C-CA233262 (PKS, SS), U2C-CA233291 (CNH, KSL), R01-DK103831 (CNH, KSL), NIH training grant T32-GM007748 (SC), P30-CA06516 (for histology), Ludwig Cancer Research, the Gray Foundation, and the David Liposarcoma Research Initiative.