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Micro-region transcriptomics of fixed human tissue using Pick-Seq

View ORCID ProfileZoltan Maliga, View ORCID ProfileAjit J. Nirmal, View ORCID ProfileNolan G. Ericson, View ORCID ProfileSarah A. Boswell, Lance U’Ren, Rebecca Podyminogin, Jennifer Chow, View ORCID ProfileYu-An Chen, View ORCID ProfileAlyce A. Chen, View ORCID ProfileDavid M. Weinstock, View ORCID ProfileChristine G. Lian, View ORCID ProfileGeorge F. Murphy, Eric P. Kaldjian, View ORCID ProfileSandro Santagata, View ORCID ProfilePeter K. Sorger
doi: https://doi.org/10.1101/2021.03.18.431004
Zoltan Maliga
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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Ajit J. Nirmal
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
2Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
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Nolan G. Ericson
3RareCyte Inc., 2601 4th Avenue. Suite 500, Seattle, WA 98121, USA
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Sarah A. Boswell
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
4Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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Lance U’Ren
3RareCyte Inc., 2601 4th Avenue. Suite 500, Seattle, WA 98121, USA
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Rebecca Podyminogin
3RareCyte Inc., 2601 4th Avenue. Suite 500, Seattle, WA 98121, USA
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Jennifer Chow
3RareCyte Inc., 2601 4th Avenue. Suite 500, Seattle, WA 98121, USA
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Yu-An Chen
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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Alyce A. Chen
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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David M. Weinstock
2Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
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Christine G. Lian
4Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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George F. Murphy
4Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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Eric P. Kaldjian
3RareCyte Inc., 2601 4th Avenue. Suite 500, Seattle, WA 98121, USA
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Sandro Santagata
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
5Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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Peter K. Sorger
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
4Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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  • For correspondence: peter_sorger@hms.harvard.edu alyce_chen@hms.harvard.edu
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ABSTRACT

Spatial transcriptomics and multiplexed imaging are complementary methods for studying tissue biology and disease. Recently developed spatial transcriptomic methods use fresh-frozen specimens but most diagnostic specimens, clinical trials, and tissue archives rely on formaldehyde-fixed tissue. Here we describe the Pick-Seq method for deep spatial transcriptional profiling of fixed tissue. Pick-Seq is a form of micro-region sequencing in which small regions of tissue, containing 5-20 cells, are mechanically isolated on a microscope and then sequenced. We demonstrate the use of Pick-Seq with several different fixed and frozen human specimens. Application of Pick-Seq to a human melanoma with complex histology reveals significant differences in transcriptional programs associated with tumor invasion, proliferation, and immuno-editing. Parallel imaging confirms changes in immuno-phenotypes and cancer cell states. This work demonstrates the ability of Pick-Seq to generate deep spatial transcriptomic data from fixed and archival tissue with multiplexed imaging in parallel.

Competing Interest Statement

NE, LU, RP, JC, and EJK are or have been employees of RareCyte Inc. PKS is a member of the SAB or BOD 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. SS is a consultant for RareCyte Inc. All other authors declare they have no competing interests.

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 March 19, 2021.
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Micro-region transcriptomics of fixed human tissue using Pick-Seq
Zoltan Maliga, Ajit J. Nirmal, Nolan G. Ericson, Sarah A. Boswell, Lance U’Ren, Rebecca Podyminogin, Jennifer Chow, Yu-An Chen, Alyce A. Chen, David M. Weinstock, Christine G. Lian, George F. Murphy, Eric P. Kaldjian, Sandro Santagata, Peter K. Sorger
bioRxiv 2021.03.18.431004; doi: https://doi.org/10.1101/2021.03.18.431004
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Micro-region transcriptomics of fixed human tissue using Pick-Seq
Zoltan Maliga, Ajit J. Nirmal, Nolan G. Ericson, Sarah A. Boswell, Lance U’Ren, Rebecca Podyminogin, Jennifer Chow, Yu-An Chen, Alyce A. Chen, David M. Weinstock, Christine G. Lian, George F. Murphy, Eric P. Kaldjian, Sandro Santagata, Peter K. Sorger
bioRxiv 2021.03.18.431004; doi: https://doi.org/10.1101/2021.03.18.431004

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