Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
University of Helsinki and Wihuri Research Institute, Helsinki, Finland.
Biol Open. 2022 Dec 15;11(12). doi: 10.1242/bio.059623. Epub 2022 Dec 13.
Preclinical tumor models with native tissue microenvironments provide essential tools to understand how heterogeneous tumor phenotypes relate to drug response. Here we present syngeneic graft models of aggressive, metastasis-prone histopathology-specific NSCLC tumor types driven by KRAS mutation and loss of LKB1 (KL): adenosquamous carcinoma (ASC) and adenocarcinoma (AC). We show that subcutaneous injection of primary KL; ASC cells results in squamous cell carcinoma (SCC) tumors with high levels of stromal infiltrates, lacking the source heterogeneous histotype. Despite forming subcutaneous tumors, intravenously injected KL;AC cells were unable to form lung tumors. In contrast, intravenous injection of KL;ASC cells leads to their lung re-colonization and lesions recapitulating the mixed AC and SCC histopathology, tumor immune suppressive microenvironment and oncogenic signaling profile of source tumors, demonstrating histopathology-selective phenotypic dominance over genetic drivers. Pan-ERBB inhibition increased survival, while selective ERBB1/EGFR inhibition did not, suggesting a role of the ERBB network crosstalk in resistance to ERBB1/EGFR. This immunocompetent NSCLC lung colonization model hence phenocopies key properties of the metastasis-prone ASC histopathology, and serves as a preclinical model to dissect therapy responses and metastasis-associated processes.
具有天然组织微环境的临床前肿瘤模型为了解肿瘤异质性表型与药物反应的关系提供了重要工具。在这里，我们提出了由 KRAS 突变和 LKB1（KL）缺失驱动的侵袭性、易转移的组织病理学特异性 NSCLC 肿瘤类型的同源移植物模型：腺鳞癌（ASC）和腺癌（AC）。我们表明，KL；ASC 细胞的原发性 KL 的皮下注射导致具有高水平基质浸润的鳞状细胞癌（SCC）肿瘤，缺乏同源异质性组织型的来源。尽管形成了皮下肿瘤，但静脉注射的 KL；AC 细胞无法形成肺肿瘤。相比之下，KL；ASC 细胞的静脉注射导致它们在肺部重新定植，病变再现了混合的 AC 和 SCC 组织病理学、肿瘤免疫抑制微环境和源肿瘤的致癌信号特征，表明组织病理学选择性表型对遗传驱动因素的优势。泛 ERBB 抑制增加了存活率，而选择性 ERBB1/EGFR 抑制则没有，这表明 ERBB 网络串扰在 ERBB1/EGFR 耐药中起作用。因此，这种免疫活性 NSCLC 肺定植模型模拟了易转移的 ASC 组织病理学的关键特性，并作为一种临床前模型，用于剖析治疗反应和转移相关过程。
