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Clinical Cancer Research
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Precision Medicine and Imaging

Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen

Yurina Ogawa, Yohei Masugi, Tokiya Abe, Ken Yamazaki, Akihisa Ueno, Yoko Fujii-Nishimura, Shutaro Hori, Hiroshi Yagi, Yuta Abe, Minoru Kitago and Michiie Sakamoto
Yurina Ogawa
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Yohei Masugi
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
2Division of Diagnostic Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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  • ORCID record for Yohei Masugi
Tokiya Abe
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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  • ORCID record for Tokiya Abe
Ken Yamazaki
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Akihisa Ueno
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Yoko Fujii-Nishimura
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
3Department of Pathology, International University of Health and Welfare School of Medicine, Narita, Chiba, Japan.
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Shutaro Hori
4Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Hiroshi Yagi
4Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Yuta Abe
4Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Minoru Kitago
4Department of Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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Michiie Sakamoto
1Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
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  • For correspondence: msakamot@z5.keio.jp
DOI: 10.1158/1078-0432.CCR-20-2298 Published January 2021
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Abstract

Purpose: Cancer-associated fibroblasts have emerged to be highly heterogenous and can play multifaceted roles in dictating pancreatic ductal adenocarcinoma (PDAC) progression, immunosuppression, and therapeutic response, highlighting the need for a deeper understanding of stromal heterogeneity between patients and even within a single tumor. We hypothesized that image analysis of fibroblast subpopulations and collagen in PDAC tissues might guide stroma-based patient stratification to predict clinical outcomes and tumor characteristics.

Experimental Design: A novel multiplex IHC-based image analysis system was established to digitally differentiate fibroblast subpopulations. Using whole-tissue slides from 215 treatment-naïve PDACs, we performed concurrent quantification of principal fibroblast subpopulations and collagen and defined three stroma types: collagen-rich stroma, fibroblast activation protein α (FAP)-dominant fibroblast-rich stroma, and α smooth muscle actin (ACTA2)-dominant fibroblast-rich stroma. These stroma types were assessed for the associations with cancer-specific survival by multivariable Cox regression analyses and with clinicopathologic factors, including CD8+ cell density.

Results: FAP-dominant fibroblasts and ACTA2-dominant fibroblasts represented the principal distinct fibroblast subpopulations in tumor stroma. Stroma types were associated with patient survival, SMAD4 status, and transcriptome signatures. Compared with FAP-dominant fibroblast-rich stroma, collagen-rich stroma correlated with prolonged survival [HR, 0.57; 95% confidence interval (CI), 0.33–0.99], while ACTA2-dominant fibroblast-rich stroma exhibited poorer prognosis (HR, 1.65; 95% CI, 1.06–2.58). FAP-dominant fibroblast-rich stroma was additionally characterized by restricted CD8+ cell infiltrates and intense neutrophil infiltration.

Conclusions: This study identified three distinct stroma types differentially associated with survival, immunity, and molecular features, thereby underscoring the importance of stromal heterogeneity in subtyping pancreatic cancers and supporting the development of antistromal therapies.

This article is featured in Highlights of This Issue, p. 1

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;27:107–19

  • Received June 15, 2020.
  • Revision received September 3, 2020.
  • Accepted October 6, 2020.
  • Published first October 12, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 27 (1)
January 2021
Volume 27, Issue 1
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Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen
Yurina Ogawa, Yohei Masugi, Tokiya Abe, Ken Yamazaki, Akihisa Ueno, Yoko Fujii-Nishimura, Shutaro Hori, Hiroshi Yagi, Yuta Abe, Minoru Kitago and Michiie Sakamoto
Clin Cancer Res January 1 2021 (27) (1) 107-119; DOI: 10.1158/1078-0432.CCR-20-2298

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Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen
Yurina Ogawa, Yohei Masugi, Tokiya Abe, Ken Yamazaki, Akihisa Ueno, Yoko Fujii-Nishimura, Shutaro Hori, Hiroshi Yagi, Yuta Abe, Minoru Kitago and Michiie Sakamoto
Clin Cancer Res January 1 2021 (27) (1) 107-119; DOI: 10.1158/1078-0432.CCR-20-2298
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