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An Omic and Multidimensional Spatial Atlas from Serial Biopsies of an Evolving Metastatic Breast Cancer

View ORCID ProfileBrett E. Johnson, Allison L. Creason, Jayne M. Stommel, Jamie M. Keck, Swapnil Parmar, Courtney B. Betts, Aurora Blucher, Christopher Boniface, Elmar Bucher, Erik Burlingame, Todd Camp, Koei Chin, Jennifer Eng, Joseph Estabrook, Heidi S. Feiler, Zhi Hu, Annette Kolodzie, Ben L. Kong, Marilyne Labrie, Jinho Lee, Patrick Leyshock, Souraya Mitri, Janice Patterson, Jessica L. Riesterer, Shamilene Sivagnanam, Julia Somers, Damir Sudar, Guillaume Thibault, Christina Zheng, View ORCID ProfileXiaolin Nan, Laura M. Heiser, View ORCID ProfilePaul T. Spellman, View ORCID ProfileGeorge Thomas, Emek Demir, View ORCID ProfileYoung Hwan Chang, Lisa M. Coussens, Alexander R. Guimaraes, Christopher Corless, Jeremy Goecks, Raymond Bergan, Zahi Mitri, Gordon B. Mills, View ORCID ProfileJoe W. Gray
doi: https://doi.org/10.1101/2020.12.03.408500
Brett E. Johnson
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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  • ORCID record for Brett E. Johnson
Allison L. Creason
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Jayne M. Stommel
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Jamie M. Keck
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Swapnil Parmar
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Courtney B. Betts
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
3Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
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Aurora Blucher
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
3Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
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Christopher Boniface
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
4Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, 97239, USA
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Elmar Bucher
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Erik Burlingame
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
5Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239, USA
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Todd Camp
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Koei Chin
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Jennifer Eng
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Joseph Estabrook
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
6Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA
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Heidi S. Feiler
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Zhi Hu
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Annette Kolodzie
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Ben L. Kong
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
7Department of Pharmacy Services, Oregon Health & Science University, Portland, OR, 97239, USA
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Marilyne Labrie
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
3Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
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Jinho Lee
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Patrick Leyshock
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Souraya Mitri
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Janice Patterson
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
8Knight Diagnostic Laboratories, Oregon Health and Science University, Portland, OR, 97239, USA
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Jessica L. Riesterer
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
9Multiscale Microscopy Core, Oregon Health & Science University, Portland, OR, 97239, USA
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Shamilene Sivagnanam
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
3Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
5Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239, USA
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Julia Somers
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
6Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA
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Damir Sudar
10Quantitative Imaging Systems LLC, Portland, OR, 97239, USA
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Guillaume Thibault
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Christina Zheng
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Xiaolin Nan
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
4Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR, 97239, USA
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Laura M. Heiser
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Paul T. Spellman
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
6Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA
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George Thomas
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
11Department of Pathology & Laboratory Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
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Emek Demir
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
6Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, USA
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Young Hwan Chang
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
5Computational Biology Program, Oregon Health & Science University, Portland, OR, 97239, USA
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Lisa M. Coussens
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
3Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
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Alexander R. Guimaraes
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
12Department of Diagnostic Radiology, Oregon Health & Science University, Portland, OR, 97239, USA
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Christopher Corless
7Department of Pharmacy Services, Oregon Health & Science University, Portland, OR, 97239, USA
11Department of Pathology & Laboratory Medicine, Oregon Health & Science University, Portland, OR, 97239, USA
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Jeremy Goecks
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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Raymond Bergan
13Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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Zahi Mitri
14Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
15Department of Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
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Gordon B. Mills
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
3Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, 97239, USA
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Joe W. Gray
1Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA
2Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97239, USA
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  • ORCID record for Joe W. Gray
  • For correspondence: grayjo@ohsu.edu
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Summary

Mechanisms of therapeutic resistance manifest in metastatic cancers as tumor cell intrinsic alterations and extrinsic microenvironmental influences that can change during treatment. To support the development of methods for the identification of these mechanisms in individual patients, we present here an Omic and Multidimensional Spatial (OMS) Atlas generated from four serial biopsies of a metastatic breast cancer patient during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata including treatment times and doses, anatomic imaging, and blood-based response measurements to exploratory analytics including comprehensive DNA, RNA, and protein profiles, images of multiplexed immunostaining, and 2- and 3-dimensional scanning electron micrographs. These data reveal aspects of therapy-associated heterogeneity and evolution of the cancer’s genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples showing how integrative analyses of these data provide insights into potential mechanisms of response and resistance, and suggest novel therapeutic vulnerabilities.

Competing Interest Statement

D.S. is employed by Quantitative Imaging Systems, which sells image analysis software. L.M.C. is a paid consultant for Cell Signaling Technologies, Shasqi Inc., and AbbVie Inc.; received reagent and/or research support from Plexxikon Inc., Pharmacyclics Inc., Acerta Pharma, LLC, Deciphera Pharmaceuticals, LLC, Genentech Inc., Roche Glycart AG, Syndax Pharmaceuticals Inc., Innate Pharma, and NanoString Technologies; and is a member of the Scientific Advisory Boards of Syndax Pharmaceuticals, Carisma Therapeutics, Zymeworks Inc., Verseau Therapeutics, Cytomix Therapeutics Inc., and Kineta Inc. G.B.M. has licensed technologies to Myriad Genetics and Nanostring; is on the SAB or is a consultant to Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, and Zentalis Pharmaceuticals; and has stock/options/financial interests in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. J.W.G. has licensed technologies to Abbott Diagnostics; has ownership positions in Convergent Genomics, Health Technology Innovations, Zorro Bio, and PDX Pharmaceuticals; serves as a paid consultant to New Leaf Ventures; has received research support from Thermo Fisher Scientific (formerly FEI), Zeiss, Miltenyi Biotech, Quantitative Imaging, Health Technology Innovations, and Micron Technologies; and owns stock in Abbott Diagnostics, AbbVie, Alphabet, Amazon, Amgen, Apple, General Electric, Gilead, Intel, Microsoft, Nvidia, and Zimmer Biomet.

Footnotes

  • Author List Footnotes: Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Joe Gray (grayjo{at}ohsu.edu).

  • Text revision to present the data as an atlas; Text, Figures 2-6, Figures S1-S6, Tables S1-S2 revised to include new data; additional authors added.

  • https://humantumoratlas.org/

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 4.0 International license.
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An Omic and Multidimensional Spatial Atlas from Serial Biopsies of an Evolving Metastatic Breast Cancer
Brett E. Johnson, Allison L. Creason, Jayne M. Stommel, Jamie M. Keck, Swapnil Parmar, Courtney B. Betts, Aurora Blucher, Christopher Boniface, Elmar Bucher, Erik Burlingame, Todd Camp, Koei Chin, Jennifer Eng, Joseph Estabrook, Heidi S. Feiler, Zhi Hu, Annette Kolodzie, Ben L. Kong, Marilyne Labrie, Jinho Lee, Patrick Leyshock, Souraya Mitri, Janice Patterson, Jessica L. Riesterer, Shamilene Sivagnanam, Julia Somers, Damir Sudar, Guillaume Thibault, Christina Zheng, Xiaolin Nan, Laura M. Heiser, Paul T. Spellman, George Thomas, Emek Demir, Young Hwan Chang, Lisa M. Coussens, Alexander R. Guimaraes, Christopher Corless, Jeremy Goecks, Raymond Bergan, Zahi Mitri, Gordon B. Mills, Joe W. Gray
bioRxiv 2020.12.03.408500; doi: https://doi.org/10.1101/2020.12.03.408500
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An Omic and Multidimensional Spatial Atlas from Serial Biopsies of an Evolving Metastatic Breast Cancer
Brett E. Johnson, Allison L. Creason, Jayne M. Stommel, Jamie M. Keck, Swapnil Parmar, Courtney B. Betts, Aurora Blucher, Christopher Boniface, Elmar Bucher, Erik Burlingame, Todd Camp, Koei Chin, Jennifer Eng, Joseph Estabrook, Heidi S. Feiler, Zhi Hu, Annette Kolodzie, Ben L. Kong, Marilyne Labrie, Jinho Lee, Patrick Leyshock, Souraya Mitri, Janice Patterson, Jessica L. Riesterer, Shamilene Sivagnanam, Julia Somers, Damir Sudar, Guillaume Thibault, Christina Zheng, Xiaolin Nan, Laura M. Heiser, Paul T. Spellman, George Thomas, Emek Demir, Young Hwan Chang, Lisa M. Coussens, Alexander R. Guimaraes, Christopher Corless, Jeremy Goecks, Raymond Bergan, Zahi Mitri, Gordon B. Mills, Joe W. Gray
bioRxiv 2020.12.03.408500; doi: https://doi.org/10.1101/2020.12.03.408500

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