Spheroid Culture of Primary Lung Cancer Cells with Neuregulin 1/HER3 Pathway Activation Hiroko Endo, BPHRM, Jiro Okami, MD, PhD, Hiroaki Okuyama, MD,

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Spheroid Culture of Primary Lung Cancer Cells with Neuregulin 1/HER3 Pathway Activation Hiroko Endo, BPHRM, Jiro Okami, MD, PhD, Hiroaki Okuyama, MD, PhD, Toru Kumagai, MD, PhD, Junji Uchida, MD, PhD, Jumpei Kondo, MD, PhD, Tetsuo Takehara, MD, PhD, Yasuko Nishizawa, MD, PhD, Fumio Imamura, MD, PhD, Masahiko Higashiyama, MD, PhD, Masahiro Inoue, MD, PhD Journal of Thoracic Oncology Volume 8, Issue 2, Pages 131-139 (February 2013) DOI: 10.1097/JTO.0b013e3182779ccf Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Preparation and characterization of CTOSs from patients’ lung tumors. A, H&E staining of original tumor and phase contrast images of organoid fraction at the indicated times after OMLC-58 preparation. Low- (upper panels) and high-magnification (lower panels) images are shown. Scale bar: 200 μm. B, Phase contrast images of CTOSs from three independent pleural effusion samples. Scale bar: 200 μm. C, Flow cytometric analysis of the indicated cell-surface antigens by specific antibodies (solid line) or isotype controls (gray filled). D, OMLC-40 subjected to H&E staining and immunohistochemistry of E-cadherin (green), α-SMA (red), CD68 (red), and Hoechst33342 (blue). Scale bar: 75 μm. H&E, hematoxylin and eosin. Journal of Thoracic Oncology 2013 8, 131-139DOI: (10.1097/JTO.0b013e3182779ccf) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 CTOS-derived xenotumors preserved the original characteristics of parental tumors. A, H&E staining of the indicated cases. B, Immunohistochemistry of EGFR from the indicated cases. Original tumor (left column), CTOS (middle column), and xenograft tumor (right column). Adeno, adenocarcinoma; Squamous, squamous cell carcinoma; LCNEC, large-cell neuroendocrine carcinoma. Scale bar: 100 μm. Journal of Thoracic Oncology 2013 8, 131-139DOI: (10.1097/JTO.0b013e3182779ccf) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Effect of erlotinib on CTOS growth and signal transduction. A, In vitro dose–response curve of erlotinib sensitivity with 10 clinical cases. Origins of the cases are indicated in ascending order of IC50. B, Western blot of EGFR signaling pathway from 10 clinical cases, in ascending order of IC50. CTOSs were cultured under growth-factor–starved conditions and pulsed for 15 minutes with 10 ng/ml EGF in the presence or absence of 1 μM erlotinib. C, Effects of erlotinib on the growth of xenograft tumors derived from OMLC-145 (EGFR overexpresser), OMLC-10 (EGFR-nonexpresser), OMLC-149 (EGFR wt), and OMLC-40 (EGFR wt). The CTOSs were transplanted in NOD/SCID mice (n = 5). Erlotinib was administered orally once a day ×5 for 2 weeks, indicated as black bars. Tumor volume at each time point (V) was corrected by that on day 1 (V0). Open circles, vehicle-treated controls; closed circles, erlotinib-treated groups. IC50, inhibitory concentration. *p < 0.05 Journal of Thoracic Oncology 2013 8, 131-139DOI: (10.1097/JTO.0b013e3182779ccf) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 NRG1stimulated CTOS growth in vitro. Growth ratio of CTOSs from six cases at day 7 relative to day 0. The CTOSs were embedded in Matrigel growth factor reduced and cultured in StemPro hESC or defined conditions containing NRG1, Long-IGF (IGF), bFGF, Activin A (Activin), or EGF at 10 ng/mlL or 100 ng/ml. *p < 0.05. Journal of Thoracic Oncology 2013 8, 131-139DOI: (10.1097/JTO.0b013e3182779ccf) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 5 Effect of NRG1 on pathway activation in CTOSs. A, Western blot for ErbB family signaling pathway of OMLC-128 and OMLC-53. CTOSs were cultured under growth-factor–starved conditions and stimulated by 10 ng/ml of each indicated growth factor for 15 minutes. B, Immunohistochemistry of phospho-HER3 and phospho-AKT after NRG1 stimulation. OMLC-128 or OMLC-53 CTOSs were cultured under starvation conditions and stimulated by 10 ng/ml NRG1 for 6 hours (pHER3) or 1 hour (pAKT). EGFR, ZO1, and E-cadherin staining indicate the polarity of the CTOSs. C, Inhibitory effect of anti-HER3 antibody on growth of OMLC-128 CTOSs. CTOSs were embedded in Matrigel growth factor reduced, cultured in basal medium containing 10 ng/ml NRG1 or StemPro hESC, and treated with the indicated doses of anti-HER3 antibody. *p < 0.05. D, Effect of anti-HER3 antibody on signal transduction of OMLC-128. CTOSs were cultured in StemPro containing the indicated dose of anti-HER3 antibody for 24 hours. StemPro hESC; IGF; long-IGF1, Activin; Activin A. Journal of Thoracic Oncology 2013 8, 131-139DOI: (10.1097/JTO.0b013e3182779ccf) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions