引言：小细胞肺癌（SCLC）因治疗后复发率高而被认为是所有肺癌中预后最差的类型。虽然肺癌是美国第二常见的恶性肿瘤，但只有约10%的肺癌是SCLC，因此被归类为罕见且难治疾病。SCLC的治疗发现一直具有挑战性，现有的临床前模型经常无法重现真实的肿瘤病理生理学。为了解决这个问题，我们开发了一种生物工程三维（3D）SCLC共培养器官样模型，作为研究SCLC肿瘤动力学和化疗后SCLC-成纤维细胞相互作用的表型工具。方法：我们使用功能化的藻酸盐微球作为支架来模拟肺泡结构，并与原代成年肺成纤维细胞（ALF）共培养SCLC细胞系。我们发现，在该模型中，SCLC细胞大量增殖，并侵袭藻酸盐微球支架，仅需7天内形成肿瘤。我们将生物工程肿瘤与患者肿瘤进行比较，发现它们能够重现患者肿瘤的病理学和免疫表型。在用标准化疗药物依托泊苷和顺铂治疗时，我们观察到一些细胞在化疗中存活下来，并在器官样模型中再次形成肿瘤。结果与讨论：SCLC细胞与ALFs的共培养表明成纤维细胞在加速模型中SCLC细胞的再生增长中起到关键作用。这可能是由于旁分泌作用，因为来自相同成纤维细胞的调节培养基也可以支持这种加速再生。该模型可用于研究SCLC的细胞相互作用和对化疗的反应，并且可扩展且适合用于高通量表型或靶向药物筛选，以寻找新的SCLC治疗方法。版权所有© 2023 Sen, Koloff, Kundu, Wilkinson, Yang, Shia, Meneses, Rickabaugh和Gomperts。

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.Copyright © 2023 Sen, Koloff, Kundu, Wilkinson, Yang, Shia, Meneses, Rickabaugh and Gomperts.