Sen Chandani, Koloff Caroline, Kundu Souvik, Wilkinson Dan C, Yang Juliette, Shia David W, Meneses Luisa K, Rickabaugh Tammy M, Gomperts Brigitte N
bioRxiv. 2023 Jan 12:2023.01.03.522668. doi: 10.1101/2023.01.03.522668.
Small-cell-lung-cancer (SCLC) has the worst prognosis of all lung cancers because of a high incidence of relapse after therapy. We developed a bioengineered 3-dimensional (3D) SCLC co-culture organoid as a phenotypic tool to study SCLC tumor kinetics and SCLC-fibroblast interactions during relapse. 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 better than the PDX model developed from the same SCLC cell line. When treated with standard chemotherapy drugs, etoposide and cisplatin, the organoid recapitulated relapse after chemotherapy. 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 was a paracrine effect as conditioned medium from the same fibroblasts was responsible for this accelerated cell regrowth. This model is also amenable to high throughput phenotypic or targeted drug screening to find new therapeutics for SCLC.
小细胞肺癌（SCLC）由于治疗后复发率高，在所有肺癌中预后最差。我们开发了一种生物工程三维（3D）小细胞肺癌共培养类器官，作为一种表型工具，用于研究复发期间小细胞肺癌的肿瘤动力学和小细胞肺癌与成纤维细胞的相互作用。我们使用功能化藻酸盐微珠作为支架来模拟肺泡结构，并将小细胞肺癌细胞系与原代成人肺成纤维细胞（ALF）共培养。我们发现该模型中的小细胞肺癌在短短7天内就大量增殖，侵入微珠支架并形成肿瘤。我们将生物工程肿瘤与患者肿瘤进行比较，发现它们比由相同小细胞肺癌细胞系开发的PDX模型更能重现患者肿瘤的病理学和免疫表型。当用标准化疗药物依托泊苷和顺铂治疗时，类器官重现了化疗后的复发情况。小细胞肺癌细胞与ALF的共培养表明，成纤维细胞在诱导模型中小细胞肺癌细胞更快、更强有力地重新生长方面发挥着关键作用。这是一种旁分泌效应，因为来自相同成纤维细胞的条件培养基导致了这种加速的细胞重新生长。该模型也适用于高通量表型或靶向药物筛选，以寻找小细胞肺癌的新疗法。
