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Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis

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Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis Author Manuscript Published OnlineFirst on August 22, 2019; DOI: 10.1158/0008-5472.CAN-19-0454 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Meflin-positive cancer-associated fibroblasts inhibit pancreatic 2 carcinogenesis 3 Yasuyuki Mizutani1,2,16, Hiroki Kobayashi1,3,16, Tadashi Iida1,2,16, Naoya Asai1,4, Atsushi 4 Masamune5, Akitoshi Hara1, Nobutoshi Esaki1, Kaori Ushida1, Shinji Mii1, Yukihiro 5 Shiraki1, Kenju Ando1, Liang Weng1, Seiichiro Ishihara6, Suzanne M. Ponik7, Matthew W. 6 Conklin7, Hisashi Haga6, Arata Nagasaka8, Takaki Miyata9, Makoto Matsuyama10, Tomoe 7 Kobayashi10, Tsutomu Fujii11, Suguru Yamada12, Junpei Yamaguchi13, Tongtong Wang3, 8 Susan L. Woods3, Daniel L. Worthley3, Teppei Shimamura14, Mitsuhiro Fujishiro2, Yoshiki 9 Hirooka15, Atsushi Enomoto1,* & Masahide Takahashi1,4,* 10 1Department of Pathology, 2Gastroenterology and Hepatology, 4Division of Molecular 11 Pathology, Center for Neurological Disease and Cancer, 9Anatomy and Cell Biology, 12 12Department of Gastroenterological Surgery (Surgery II), 13Division of Surgical Oncology, 13 Department of Surgery, and 14Division of Systems Biology, Nagoya University Graduate 14 School of Medicine, Nagoya, 466-8550, Japan 15 3School of Medicine, University of Adelaide and South Australian Health and Medical 16 Research Institute, Adelaide, South Australia, Australia 17 5Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, 18 Japan 19 6Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan 20 7Department of Cell and Regenerative Biology, University of Wisconsin-Madison, 21 Madison, WI, USA 22 8Division of Anatomy, Department of Human Development and Fostering, Meikai 23 University School of Dentistry, Sakado, Japan 24 10Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan 25 11Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical 26 Sciences, University of Toyama, Toyama, Japan 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 22, 2019; DOI: 10.1158/0008-5472.CAN-19-0454 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 15Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, 2 Toyoake, Japan 3 16These authors contributed equally to this study. 4 5 Running title: Meflin defines cancer-restraining CAFs in pancreatic cancer 6 7 Keywords: Meflin, cancer-associated fibroblasts, pancreatic cancer, pancreatic stellate 8 cells, tumor microenvironment, lysyl oxidase 9 10 Financial support: This work was supported by a Grant-in-Aid for Scientific Research (S) 11 (26221304 to M.T.) and a Grant-in-Aid for Scientific Research (B) (15H04719 and 12 18H02638 to A.E.; 15H04804 and 19H03631 to A.M.) commissioned by the Ministry of 13 Education, Culture, Sports, Science and Technology of Japan; Nagoya University Hospital 14 Funding for Clinical Research (to A.E.); The Hori Sciences And Arts Foundation (to A.E.); 15 Kobayashi Foundation for Cancer Research (to A.E.); AMED-CREST (Japan Agency for 16 Medical Research and Development, Core Research for Evolutional Science and 17 Technology; to A.E. and H.H.); the Project for Cancer Research and Therapeutic Evolution 18 (P-CREATE) from AMED (to A.E.); the Mochida Memorial Foundation for Medical and 19 Pharmaceutical Research (to A.E.); and the Smoking Research Foundation (to A.M.). H.K. 20 is supported by the Japan Society for the Promotion of Science (JSPS) Overseas Challenge 21 Program for Young Researchers and Takeda Science Foundation Fellowship. 22 23 Corresponding authors: Atsushi Enomoto and Masahide Takahashi 24 Department of Pathology, Nagoya University Graduate School of Medicine, 65 25 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. 26 Tel: +81-52-744-2093; Fax: +81-52-744-2098; Email: [email protected] or 27 [email protected] 28 2 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 22, 2019; DOI: 10.1158/0008-5472.CAN-19-0454 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Conflicts of interest: The authors have no conflicts of interest to declare. 2 3 Word count: 5024 words 4 5 Total number of figures and tables: 7 figures 6 7 8 Abstract (247 words) 9 Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor 10 microenvironment. Recent observations in genetically engineered mouse models and clinical 11 studies have suggested that there may exist at least two functionally different populations of 12 CAFs, i.e., cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). 13 Although various pCAF markers have been identified, the identity of rCAFs remains 14 unknown because of the lack of rCAF-specific marker(s). In the present study, we found that 15 Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal 16 stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic 17 stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In-situ 18 hybridization analysis of 71 human PDAC tissues revealed that the infiltration of 19 Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, 20 Meflin deficiency led to significant tumor progression with poorly differentiated histology in 21 a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor 22 differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a 23 Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs 3 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 22, 2019; DOI: 10.1158/0008-5472.CAN-19-0454 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 suppressed the growth of xenograft tumors. Lineage-tracing revealed that Meflin-positive 2 cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for 3 Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low 4 expression resulted in straightened stromal collagen fibers, which represent a signature for 5 aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data 6 suggest that Meflin is a marker of rCAFs that suppress PDAC progression. 7 8 9 Significance: Meflin marks and functionally contributes to a subset of cancer-associated 10 fibroblasts that exert anti-tumoral effects. 11 12 13 Introduction 14 Tumors are not a homogenous mass of cancer cells, but also comprise many types of 15 non-cancer cells, including cancer-associated fibroblasts (CAFs), myeloid cells, and 16 lymphocytes (1, 2). These cells, together with tumor vessels and the extracellular matrix 17 (ECM), shape the tumor microenvironment (TME), which is vital not only for the 18 development and progression of cancer but also tumor immunity and resistance to 19 anti-cancer therapies (1, 2). 20 CAFs constitute a major component of the TME and produce various types of ECM 21 proteins, such as collagen, and soluble signaling molecules (3-8). CAFs promote the 4 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 22, 2019; DOI: 10.1158/0008-5472.CAN-19-0454 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 proliferation and invasion of cancer cells either directly via soluble signaling molecules or 2 indirectly through the regulation of angiogenesis and immunity (3-9). Stromal fibrosis and 3 stiffening driven by the ECM produced by CAFs, which are particularly conspicuous in 4 aggressive cancers such as pancreatic ductal adenocarcinoma (PDAC), also increase cancer 5 cell malignancy and therapeutic resistance (10-12). Many studies have shown positive 6 correlations between CAF infiltration, monitored by analyzing standard CAF markers such 7 as α-smooth muscle actin (α-SMA), fibroblast-specific protein 1 (FSP1), fibroblast activation 8 protein (FAP), and podoplanin, and poor outcome of cancer patients (3, 4, 6, 8, 13-18). Thus, 9 the biology of CAFs, including their origins, specific markers, functions, and clinical 10 relevance, has gained increasing research interest in recent years (3-8). Clinical trials of 11 therapeutics that target CAFs are also emerging, with investigations on the underlying 12 mechanisms (4, 8, 19, 20). 13 One caveat in targeting CAFs, however, was pointed out by recent observations that the 14 functions of individual CAFs are not necessarily the same (3-6, 8, 21-24). Genetic depletion 15 of proliferating α-SMA-positive (α-SMA+) CAFs and conditional blocking of the Sonic 16 Hedgehog (Shh) signaling pathway, which is crucial for promoting desmoplasia in PDAC 17 (25), led to the progression of PDAC in mouse models, suggesting that certain populations of 18 CAFs, if not all, may function to suppress cancer progression (21-24). Clinical studies that 19 evaluated the use of CAF inhibitors in PDAC patients were not successful, raising the 20 question whether CAFs
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