A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features

Johanna Klughammer; Daniel L Abravanel; Åsa Segerstolpe; Timothy R Blosser; Yury Goltsev; Yi Cui; Daniel R Goodwin; Anubhav Sinha; Orr Ashenberg; Michal Slyper; Sébastien Vigneau; Judit Jané-Valbuena; Shahar Alon; Chiara Caraccio; Judy Chen; Ofir Cohen; Nicole Cullen; Laura K DelloStritto; Danielle Dionne; Janet Files; Allison Frangieh; Karla Helvie; Melissa E Hughes; Stephanie Inga; Abhay Kanodia; Ana Lako; Colin MacKichan; Simon Mages; Noa Moriel; Evan Murray; Sara Napolitano; Kyleen Nguyen; Mor Nitzan; Rebecca Ortiz; Miraj Patel; Kathleen L Pfaff; Caroline B M Porter; Asaf Rotem; Sarah Strauss; Robert Strasser; Aaron R Thorner; Madison Turner; Isaac Wakiro; Julia Waldman; Jingyi Wu; Jorge Gómez Tejeda Zañudo; Diane Zhang; Nancy U Lin; Sara M Tolaney; Eric P Winer; Edward S Boyden; Fei Chen; Garry P Nolan; Scott J Rodig; Xiaowei Zhuang; Orit Rozenblatt-Rosen; Bruce E Johnson; Aviv Regev; Nikhil Wagle

doi:10.1038/s41591-024-03215-z

A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features

Nat Med. 2024 Oct 30. doi: 10.1038/s41591-024-03215-z. Online ahead of print.

Authors

Johanna Klughammer^#^{1

2}, Daniel L Abravanel^#^{3

4}, Åsa Segerstolpe^#⁵, Timothy R Blosser^#⁶, Yury Goltsev^#⁷, Yi Cui⁸, Daniel R Goodwin⁸, Anubhav Sinha⁸, Orr Ashenberg⁵, Michal Slyper⁵, Sébastien Vigneau⁹, Judit Jané-Valbuena⁵, Shahar Alon^{8

10}, Chiara Caraccio⁷, Judy Chen⁹, Ofir Cohen^{11

12

13}, Nicole Cullen¹⁴, Laura K DelloStritto⁹, Danielle Dionne⁵, Janet Files¹¹, Allison Frangieh⁹, Karla Helvie⁹, Melissa E Hughes¹¹, Stephanie Inga⁹, Abhay Kanodia⁹, Ana Lako¹⁴, Colin MacKichan⁹, Simon Mages^{5

15}, Noa Moriel¹⁶, Evan Murray¹², Sara Napolitano⁹, Kyleen Nguyen¹¹, Mor Nitzan^{16

17

18}, Rebecca Ortiz⁹, Miraj Patel⁹, Kathleen L Pfaff¹⁴, Caroline B M Porter⁵, Asaf Rotem^{9

19}, Sarah Strauss¹¹, Robert Strasser¹⁵, Aaron R Thorner⁹, Madison Turner^{14

20}, Isaac Wakiro⁹, Julia Waldman⁵, Jingyi Wu⁹, Jorge Gómez Tejeda Zañudo^{11

12}, Diane Zhang¹², Nancy U Lin¹¹, Sara M Tolaney¹¹, Eric P Winer¹¹, Edward S Boyden^{21

22

23

24

25

26}, Fei Chen^{12

27}, Garry P Nolan⁷, Scott J Rodig^{14

28

29}, Xiaowei Zhuang^{6

24

30}, Orit Rozenblatt-Rosen^{5

31}, Bruce E Johnson^{11

32

9}, Aviv Regev^{33

34}, Nikhil Wagle^{35

36

37

38

39}

Affiliations

¹ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
² Gene Center and Department of Biochemistry, Ludwig Maximilians Universität München, Munich, Germany. [email protected].
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
⁴ Harvard Medical School, Boston, MA, USA. [email protected].
⁵ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁶ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁷ Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Media Arts and Sciences, McGovern Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁰ Faculty of Engineering, Gonda Brain Research Center and Institute of Nanotechnology, Bar-Ilan University, Ramat Gan, Israel.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹² Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹³ Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Guiron University, Beersheba, Israel.
¹⁴ Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
¹⁵ Gene Center and Department of Biochemistry, Ludwig Maximilians Universität München, Munich, Germany.
¹⁶ School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁷ Racah Institute of Physics, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁸ Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁹ AstraZeneca R&D, Boston, MA, USA.
²⁰ Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
²¹ Department of Media Arts and Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
²² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
²³ Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁴ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
²⁵ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁶ K. Lisa Yang Center for Bionics, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁷ Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
²⁸ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
²⁹ Department of Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
³⁰ Department of Physics, Harvard University, Cambridge, MA, USA.
³¹ Genentech, Inc., South San Francisco, CA, USA.
³² Harvard Medical School, Boston, MA, USA.
³³ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
³⁴ Genentech, Inc., South San Francisco, CA, USA. [email protected].
³⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
³⁶ Harvard Medical School, Boston, MA, USA. [email protected].
³⁷ Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
³⁸ Broad Institute of Harvard and MIT, Cambridge, MA, USA. [email protected].
³⁹ Genentech, Inc., South San Francisco, CA, USA. [email protected].

^# Contributed equally.

PMID: 39478111
DOI: 10.1038/s41591-024-03215-z

Abstract

Although metastatic disease is the leading cause of cancer-related deaths, its tumor microenvironment remains poorly characterized due to technical and biospecimen limitations. In this study, we assembled a multi-modal spatial and cellular map of 67 tumor biopsies from 60 patients with metastatic breast cancer across diverse clinicopathological features and nine anatomic sites with detailed clinical annotations. We combined single-cell or single-nucleus RNA sequencing for all biopsies with a panel of four spatial expression assays (Slide-seq, MERFISH, ExSeq and CODEX) and H&E staining of consecutive serial sections from up to 15 of these biopsies. We leveraged the coupled measurements to provide reference points for the utility and integration of different experimental techniques and used them to assess variability in cell type composition and expression as well as emerging spatial expression characteristics across clinicopathological and methodological diversity. Finally, we assessed spatial expression and co-localization features of macrophage populations, characterized three distinct spatial phenotypes of epithelial-to-mesenchymal transition and identified expression programs associated with local T cell infiltration versus exclusion, showcasing the potential of clinically relevant discovery in such maps.

Abstract

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