Development of a small cell lung cancer organoid model to study cellular interactions and survival after chemotherapy

Chandani Sen; Caroline R Koloff; Souvik Kundu; Dan C Wilkinson; Juliette M Yang; David W Shia; Luisa K Meneses; Tammy M Rickabaugh; Brigitte N Gomperts

doi:10.3389/fphar.2023.1211026

Development of a small cell lung cancer organoid model to study cellular interactions and survival after chemotherapy

Front Pharmacol. 2023 Aug 7:14:1211026. doi: 10.3389/fphar.2023.1211026. eCollection 2023.

Authors

Affiliations

¹ Department of Pediatrics, David Geffen School of Medicine, UCLA Children's Discovery and Innovation Institute, Mattel Children's Hospital, University of California, Los Angeles, CA, United States.
² Intel Labs, San Diego, CA, United States.
³ Pulmonary Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, United States.
⁴ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, United States.
⁵ Eli and Edythe Broad Stem Cell Research Center, University of California, Los Angeles, CA, United States.

Abstract

Introduction: Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because of a high incidence of relapse after therapy. While lung cancer is the second most common malignancy in the US, only about 10% of cases of lung cancer are SCLC, therefore, it is categorized as a rare and recalcitrant disease. Therapeutic discovery for SCLC has been challenging and the existing pre-clinical models often fail to recapitulate actual tumor pathophysiology. To address this, we developed a bioengineered 3-dimensional (3D) SCLC co-culture organoid model as a phenotypic tool to study SCLC tumor kinetics and SCLC-fibroblast interactions after chemotherapy. Method: We used functionalized alginate microbeads as a scaffold to mimic lung alveolar architecture and co-cultured SCLC cell lines with primary adult lung fibroblasts (ALF). We found that SCLCs in the model proliferated extensively, invaded the microbead scaffold and formed tumors within just 7 days. We compared the bioengineered tumors with patient tumors and found them to recapitulate the pathology and immunophenotyping of the patient tumors. When treated with standard chemotherapy drugs, etoposide and cisplatin, we observed that some of the cells survived the chemotherapy and reformed the tumor in the organoid model. Result and Discussion: Co-culture of the SCLC cells with ALFs revealed that the fibroblasts play a key role in inducing faster and more robust SCLC cell regrowth in the model. This is likely due to a paracrine effect, as conditioned media from the same fibroblasts could also support this accelerated regrowth. This model can be used to study cell-cell interactions and the response to chemotherapy in SCLC and is also scalable and amenable to high throughput phenotypic or targeted drug screening to find new therapeutics for SCLC.

Keywords: 3D model; cancer organoids; chemotherapy; conditioned media; image processing; lung fibroblast; phenotypic tool; survival.

Grants and funding

This work was supported by the American Fund for Alternatives to Animal Research (AFAAR) (CS), the Keck Foundation (BG), the Tobacco-Related Disease Research Program grant T31DT1684 (DS), the NIH/NCI Grant R01CA208303 (BG), the Tobacco Related Disease Research Program (TRDRP) High Impact Pilot Research Award (HIPRA) 26IP-0036 (BG), the TRDRP HIRA 29IP-0597 (BG), The UCLA Jonsson Comprehensive Cancer Center, (JCCC) STOP Cancer Award (BG), the Ablon Research Scholars Award (BG). Statistical analyses were supported by the NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR000124.