Upregulation of FGF9 in lung adenocarcinoma transdifferentiation to small cell lung cancer

Kota Ishioka, Hiroyuki Yasuda, Junko Hamamoto, Hideki Terai, Katsura Emoto, Tae Jung Kim, Shigemichi Hirose, Takashi Kamatani, Sachiyo Mimaki, Daisuke Arai, Keiko Ohgino, Tetsuo Tani, Keita Masuzawa, Tadashi Manabe, Taro Shinozaki, Akifumi Mitsuishi, Toshiki Ebisudani, Takahiro Fukushima, Mari Ozaki, Shinnosuke IkemuraIchiro Kawada, Katsuhiko Naoki, Morio Nakamura, Takashi Ohtsuka, Hisao Asamura, Katsuya Tsuchihara, Yuichiro Hayashi, Ahmed E. Hegab, Susumu S. Kobayashi, Takashi Kohno, Hideo Watanabe, David M. Ornitz, Tomoko Betsuyaku, Kenzo Soejima, Koichi Fukunaga

Research output: Contribution to journalArticlepeer-review

Abstract

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 TP53 and RB1 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 in vivo through cell autonomous activation of the FGFR pathway. In vivo 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.

Original languageEnglish
Pages (from-to)3916-3929
Number of pages14
JournalCancer research
Volume81
Issue number14
DOIs
StatePublished - Jul 15 2021

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