Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 81; no. 14; pp. 3916 - 3929
• Main Authors: Ishioka, Kota, Yasuda, Hiroyuki, Hamamoto, Junko, Terai, Hideki, Emoto, Katsura, Kim, Tae-Jung, Hirose, Shigemichi, Kamatani, Takashi, Mimaki, Sachiyo, Arai, Daisuke, Ohgino, Keiko, Tani, Tetsuo, Masuzawa, Keita, Manabe, Tadashi, Shinozaki, Taro, Mitsuishi, Akifumi, Ebisudani, Toshiki, Fukushima, Takahiro, Ozaki, Mari, Ikemura, Shinnosuke, Kawada, Ichiro, Naoki, Katsuhiko, Nakamura, Morio, Ohtsuka, Takashi, Asamura, Hisao, Tsuchihara, Katsuya, Hayashi, Yuichiro, Hegab, Ahmed E, Kobayashi, Susumu S, Kohno, Takashi, Watanabe, Hideo, Ornitz, David M, Betsuyaku, Tomoko, Soejima, Kenzo, Fukunaga, Koichi
• Format: Journal Article
• Language: English
• Published: United States 15.07.2021
• Subjects: Adenocarcinoma of Lung - metabolism; Adenocarcinoma of Lung - pathology; Animals; Cell Transdifferentiation; Disease Models, Animal; Female; Fibroblast Growth Factor 9 - metabolism; Heterografts; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Up-Regulation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-20-4048

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of and alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors through cell autonomous activation of the FGFR pathway. treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.