Investigating the Roles of the Epithelial-Mesenchymal Transition Program in Small Cell Lung Cancer Tumorigenesis and Chemoradiation Response

• Published in: International journal of radiation oncology, biology, physics Vol. 120; no. 2; pp. S220 - S221
• Main Authors: Nguyen, T., Chang, J.H., Gabrielson, K., Shetty, A.C., Song, Y., Lafargue, A., Jagtap, S., Council, D.N., Chan, A., Chowdhury, D.D., Khan, M. Ajmal, Connis, N., Carrieri, F.A.A., Imada, E., Sforza, D., Gardner, E., McFarland, C., Marchionni, L., Rezaee, M., Hann, C., Tran, P.T.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2024
• ISSN: 0360-3016
• DOI: 10.1016/j.ijrobp.2024.07.2304

Small cell lung cancer (SCLC) is a highly aggressive and deadly malignancy. Two major factors contributing to the high mortality of SCLC are early metastasis and rapid development of therapy resistance. Recent research suggests upregulation of the epithelial-mesenchymal transition (EMT) program and the EMT transcription factor Twist1 correlated with accelerated tumor progression and chemoradiation (CRT) resistance in SCLC. However, a causal relationship between EMT and Twist1 and these aspects of SCLC biology has not been rigorously studied. Here, we investigated whether EMT and Twist1 upregulation could promote SCLC tumorigenesis, metastasis, and resistance to CRT. To investigate the roles of EMT in SCLC biology, we have generated a novel genetically engineered mouse model (GEMM) termed RPGT (Rb1Flox; Trp53Flox; ROSA26LSL-rtTA-IRES-EGFP; Twist1-TetO7-Luc). The RPGT GEMM enables the generation of autochthonous SCLC tumors after induction with Cre recombinase adenovirus. By withdrawing or providing doxycycline to mice, we can control Twist1 expression to activate or inactivate EMT in tumors. By characterizing mouse tumor samples with histological, immunostaining, and transcriptomic profiling analyses, we evaluated the impact of Twist1 and EMT upregulation on SCLC tumor biology and plasticity as well as metastatic spread and outgrowth. To evaluate the impact of EMT activation on SCLC sensitivity to CRT, we performed in vitro viability assays on primary tumor cell lines established from RPGT tumors. We also treated RPGT mice with vs. without Twist1 overexpression with CRT to validate our in vitro data. We observed that both control (no Twist1 overexpression) and Twist1-overexpressing RPGT mice developed neuroendocrine SCLC tumors. While SCLC-A was the predominant subtype in both cohorts, RPGT tumors exhibited more plasticity, with features associated with the SCLC-N and SCLC-I subtypes. Furthermore, Twist1 overexpression dramatically increased the metastatic incidence in RPGT compared to control animals, indicating an important role of EMT in SCLC dissemination. Transcriptomic profiling of primary tumors and matching metastases in RPGT mice also revealed downregulation of Twist1 and EMT in metastases, suggesting that EMT suppression was necessary for metastatic outgrowth. Furthermore, we found that repressing Twist1 expression enhanced SCLC susceptibility to CRT both in vitro and in vivo. Overall, our data suggest that the EMT program plays an important role in promoting SCLC plasticity, metastasis, and resistance against CRT.