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

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SIMILAR CONTENT BEING VIEWED BY OTHERS PALLADIN ISOFORMS 3 AND 4 REGULATE CANCER-ASSOCIATED FIBROBLAST PRO-TUMOR FUNCTIONS IN PANCREATIC DUCTAL ADENOCARCINOMA Article Open access 15 February

2021 PD-L1-DIRECTED PLGF/VEGF BLOCKADE SYNERGIZES WITH CHEMOTHERAPY BY TARGETING CD141+ CANCER-ASSOCIATED FIBROBLASTS IN PANCREATIC CANCER Article Open access 22 October 2022 TARGETING

MFAP5 IN CANCER-ASSOCIATED FIBROBLASTS SENSITIZES PANCREATIC CANCER TO PD-L1-BASED IMMUNOCHEMOTHERAPY VIA REMODELING THE MATRIX Article Open access 08 May 2023 CHANGE HISTORY * _ 04 MAY 2022

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suppressing epithelial Hippo signaling. EMBO J. 2020;39:e103255. Article  CAS  PubMed  PubMed Central  Google Scholar  Download references 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). AUTHOR INFORMATION Author notes * Mitsuhiro

Fujishiro Present address: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan * These authors contributed equally: Tadashi Iida, Yasuyuki

Mizutani. AUTHORS AND AFFILIATIONS * 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 * 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 * Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison,

WI, USA Suzanne M. Ponik & Brian M. Burkel * Department of Oncology, Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China Liang Weng * Institute of

Transformative Bio-Molecules, Nagoya University, Nagoya, Japan Keiko Kuwata * Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan Atsushi Masamune *

Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan Seiichiro Ishihara & Hisashi Haga * Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan Hiroki

Kawashima * Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake, Aichi, Japan Yoshiki Hirooka * International Center for Cell and Gene Therapy, Fujita Health

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this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Atsushi Enomoto. ETHICS DECLARATIONS COMPETING

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

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