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    References
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    Contents lists available at ScienceDirect
    Cancer Letters
    journal homepage: www.elsevier.com/locate/canlet
    Original Articles
    Cancer-associated acinar-to-ductal metaplasia within the invasive front of T pancreatic cancer contributes to local invasion
    Shin Kibea, Kenoki Ohuchidaa,∗, Yohei Andoa, Shin Takesuea, Hiromichi Nakayamaa, Toshiya Abea, Sho Endoa, Kazuhiro Koikawaa, Takashi Okumuraa, Chika Iwamotob, Koji Shindoa, Taiki Moriyamac, Kohei Nakataa, Yoshihiro Miyasakaa, Masaya Shimamotod, Takao Ohtsukaa, Kazuhiro Mizumotod, Yoshinao Odae, Masafumi Nakamuraa,∗∗ a Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
    b Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
    c Department of Endoscopic Diagnostics and Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
    d Kyushu University Hospital Cancer Center, Fukuoka, Japan
    e Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
    Keywords:
    Pancreatic cancer
    Tumor microenvironment
    Local invasion
    ADM
    Acinar atrophy 
    The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, in-flammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis iden-tified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenviron-ment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pan-creatic parenchyma.
    1. Introduction
    Pancreatic cancer remains one of the most lethal human cancers among all malignancies, with a 5-year survival rate of approximately 8% [1]. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030 [2]. Because the disease is commonly diagnosed at a late stage, less than 20% of patients present with localized, potentially curable tumors. Even after potentially curative resection, most patients will eventually have local recurrence. The biology of pancreatic cancer contributes to early recurrence and metastasis, and resistance to chemotherapy and radiotherapy [3]. Un-derstanding the mechanisms underlying each phase of pancreatic cancer progression: initiation, invasion and metastasis, is therefore