Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment

Carina Shiau; Jingyi Cao; Dennis Gong; Mark T Gregory; Nicholas J Caldwell; 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; Jung Woo Bae; Ryan Zhao; Nathan Schurman; Jamie L Barth; Maria L Ganci; 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:10.1038/s41588-024-01890-9

Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment

Nat Genet. 2024 Sep 3. doi: 10.1038/s41588-024-01890-9. Online ahead of print.

Authors

Carina Shiau^#^{1

2

3

4}, Jingyi Cao^#⁵, Dennis Gong^{1

2

3

4

6}, Mark T Gregory⁷, Nicholas J Caldwell⁸, Xunqin Yin^{1

2

3

4}, Jae-Won Cho⁵, Peter L Wang^{1

2

3

4

9}, Jennifer Su^{1

2

3

4

9}, Steven Wang^{1

2

3

4

9}, Jason W Reeves⁷, Tae Kyung Kim⁷, Youngmi Kim⁷, Jimmy A Guo^{1

2

3

4

10}, Nicole A Lester^{1

2

3

4

9}, Jung Woo Bae^{1

2

3

4}, Ryan Zhao^{1

2

3

4}, Nathan Schurman⁷, Jamie L Barth⁸, Maria L Ganci⁸, Ralph Weissleder¹, Tyler Jacks⁹, Motaz Qadan¹¹, Theodore S Hong², Jennifer Y Wo², Hannah Roberts², Joseph M Beechem⁷, Carlos Fernandez-Del Castillo¹¹, Mari Mino-Kenudson⁸, David T Ting^{3

12}, Martin Hemberg^{13

14}, William L Hwang^{15

16

17

18

19}

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁶ Harvard-MIT Health Sciences and Technology Program, Cambridge, MA, USA.
⁷ NanoString Technologies, Seattle, WA, USA.
⁸ Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
¹⁰ Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA.
¹¹ Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹² Department of Medical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA, USA. mhemberg@bwh.harvard.edu.
¹⁴ Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mhemberg@bwh.harvard.edu.
¹⁵ Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. whwang1@mgh.harvard.edu.
¹⁶ Department of Radiation Oncology, Massachusetts General Hospital, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. whwang1@mgh.harvard.edu.
¹⁷ Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. whwang1@mgh.harvard.edu.
¹⁸ Broad Institute of MIT and Harvard, Cambridge, MA, USA. whwang1@mgh.harvard.edu.
¹⁹ Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. whwang1@mgh.harvard.edu.

^# Contributed equally.

PMID: 39227743
DOI: 10.1038/s41588-024-01890-9

Abstract

In combination with cell-intrinsic properties, interactions in the tumor microenvironment modulate therapeutic response. We leveraged single-cell spatial transcriptomics to dissect the remodeling of multicellular neighborhoods and cell-cell interactions in human pancreatic cancer associated with neoadjuvant chemotherapy and 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 coculture system. We identified enrichment in interleukin-6 family signaling that functionally confers resistance to chemotherapy. Overall, this study demonstrates that characterization of the tumor microenvironment using single-cell spatial transcriptomics allows for the identification of molecular interactions that may play a role in the emergence of therapeutic resistance and offers a spatially based analysis framework that can be broadly applied to other contexts.

Abstract

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