Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis

Carina Shiau; Jingyi Cao; Mark T Gregory; Dennis Gong; Xunqin Yin; Jae-Won Cho; Peter L Wang; Jennifer Su; Steven Wang; Jason W Reeves; Tae Kyung Kim; Youngmi Kim; Jimmy A Guo; Nicole A Lester; Nathan Schurman; Jamie L Barth; Ralph Weissleder; Tyler Jacks; Motaz Qadan; Theodore S Hong; Jennifer Y Wo; Hannah Roberts; Joseph M Beechem; Carlos Fernandez-Del Castillo; Mari Mino-Kenudson; David T Ting; Martin Hemberg; William L Hwang

doi:10.1101/2023.06.28.546848

Therapy-associated remodeling of pancreatic cancer revealed by single-cell spatial transcriptomics and optimal transport analysis

bioRxiv [Preprint]. 2023 Jun 29:2023.06.28.546848. doi: 10.1101/2023.06.28.546848.

Authors

Carina Shiau¹, Jingyi Cao², Mark T Gregory³, Dennis Gong⁴, Xunqin Yin¹, Jae-Won Cho², Peter L Wang⁵, Jennifer Su⁵, Steven Wang⁵, Jason W Reeves³, Tae Kyung Kim³, Youngmi Kim³, Jimmy A Guo⁶, Nicole A Lester⁵, Nathan Schurman³, Jamie L Barth⁷, Ralph Weissleder⁸, Tyler Jacks⁹, Motaz Qadan¹⁰, Theodore S Hong¹¹, Jennifer Y Wo¹¹, Hannah Roberts¹¹, Joseph M Beechem³, Carlos Fernandez-Del Castillo¹⁰, Mari Mino-Kenudson⁷, David T Ting¹², Martin Hemberg¹³, William L Hwang⁵

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ NanoString Technologies, Seattle, WA, USA.
⁴ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Harvard-MIT Health Sciences and Technology Program, Cambridge, MA, USA.
⁵ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁹ Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹² Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Abstract

In combination with cell intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged high-plex single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with specific malignant subtypes and neoadjuvant chemotherapy/radiotherapy. We developed Spatially Constrained Optimal Transport Interaction Analysis (SCOTIA), an optimal transport model with a cost function that includes both spatial distance and ligand-receptor gene expression. Our results uncovered a marked change in ligand-receptor interactions between cancer-associated fibroblasts and malignant cells in response to treatment, which was supported by orthogonal datasets, including an ex vivo tumoroid co-culture system. Overall, this study demonstrates that characterization of the tumor microenvironment using high-plex single-cell spatial transcriptomics allows for identification of molecular interactions that may play a role in the emergence of chemoresistance and establishes a translational spatial biology paradigm that can be broadly applied to other malignancies, diseases, and treatments.

Publication types

Preprint

Grants and funding

K08 CA270417/CA/NCI NIH HHS/United States