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Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics

Oncogene volume 41, pages 2764–2777 (2022)Cite this article

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A Correction to this article was published on 04 May 2022

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Abstract

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

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Fig. 1: Numbers of Meflin+ stromal cells correlated with response of patients with PDAC to chemotherapeutics and tumor vessel area.
Fig. 2: SeV-mediated transduction of Meflin induced increases in tumor vessel area and sensitivity to Gem.
Fig. 3: Effects of Am80 administration on the expression of Meflin in CAFs and on tumor vessel area in a PDAC xenograft mouse model.
Fig. 4: Am80 administration improved tumor sensitivity to Gem and induced Meflin expression in CAFs in a subcutaneous PDAC xenograft mouse model.
Fig. 5: Am80 administration improved tumor sensitivity to Gem and induced Meflin expression in CAFs in an orthotopic PDAC xenograft mouse model.
Fig. 6: Increased tumor chemosensitivity by Am80 administration was mediated by alterations in Meflin expression in CAFs.
Fig. 7: Meflin was involved in the regulation of Lox activity and collagen remodeling.

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Acknowledgements

We thank David Tuveson (Cold Spring Harbor Laboratory) and Chang-il Hwang (UC Davis College of Biological Sciences) for providing the mouse PDAC cell line mT5; Kohji Kusano (ID Pharma Co., Ltd.) for generating recombinant Sendai virus; Shuzo Watanabe, Kaoru Shimada (RaQualia Pharma Inc.), and Hisao Ekimoto (TMRC Co., Ltd) for helpful discussions on Am80; Kentaro Taki (Nagoya University) for help with mass spectrometry; and Kozo Uchiyama and Kaori Ushida (Nagoya University) for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research (B) (grant nos. 18H02638 to AE and 20H03467 to MT) commissioned by the Ministry of Education, Culture, Sports, Science and Technology of Japan; Nagoya University Hospital Funding for Clinical Research (to AE); AMED-CREST (Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology; grant nos. JP20gm0810007h0105 and JP20gm1210009s0102 to AE); and the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from AMED (grant nos. JP20cm0106377h0001 to AE and JP21cm0106704h0002 to YM).

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Author notes

  1. Mitsuhiro Fujishiro

    Present address: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

  2. These authors contributed equally: Tadashi Iida, Yasuyuki Mizutani.

Authors and Affiliations

  1. Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tadashi Iida, Yasuyuki Mizutani, Nobutoshi Esaki, Kunio Kataoka, Shinji Mii, Yukihiro Shiraki & Atsushi Enomoto

  2. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tadashi Iida, Yasuyuki Mizutani, Kunio Kataoka, Takuya Ishikawa, Eizaburo Ohno, Hiroki Kawashima & Mitsuhiro Fujishiro

  3. Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA

    Suzanne M. Ponik & Brian M. Burkel

  4. Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China

    Liang Weng

  5. Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan

    Keiko Kuwata

  6. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Atsushi Masamune

  7. Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan

    Seiichiro Ishihara & Hisashi Haga

  8. Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan

    Hiroki Kawashima

  9. Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Aichi, Japan

    Yoshiki Hirooka

  10. International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan

    Masahide Takahashi

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  1. Tadashi Iida
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Contributions

TIi designed and performed the experiments, analyzed the data, and wrote the paper. YM and NE designed and performed the experiments and analyzed the data. SMP and BMB performed SHG analysis. LW performed the mass spectrometric analysis. KKu performed the measurement of intratumoral concentrations of dFdC. KKa, AM, TIs, EO, and HK provided the clinical samples and intellectual input. SI and HH assisted with the analysis of tumor stiffness. SM and YS assisted with histological analysis. HK, YH, MF, and MT directed the project and provided intellectual input. AE directed the project and wrote the paper.

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Correspondence to Atsushi Enomoto.

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Iida, T., Mizutani, Y., Esaki, N. et al. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics. Oncogene 41, 2764–2777 (2022). https://doi.org/10.1038/s41388-022-02288-9

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