侵袭性粘液腺癌 (IMA) 占肺腺癌的 5%。当无法进行手术切除时，IMA 没有有效的治疗方法。 IMA 有时在病理上与具有印戒细胞特征的腺癌 (SRCC) 相混淆，因为这两种腺癌的肿瘤细胞都具有丰富的细胞内粘蛋白。这种产生粘蛋白的肺腺癌发展的分子机制仍不清楚。使用 Visium 空间转录组学方法，我们分析了 IMA 并将其与 SRCC 进行病理转录组比较。将空间转录组学数据与使用 RNA-seq 和 ChIP-seq 的体外研究相结合，我们评估了 IMA 和/或 SRCC 中高表达的转录因子 HNF4A 和 SPDEF 的下游靶标。空间转录组学分析表明，在 IMA 和/或 SRCC 中存在 6 个不同的细胞簇。 IMA 和 SRCC。值得注意的是，两种腺癌中都存在两个粘液肿瘤细胞簇（C1 和 C3），尽管比例不同。重要的是，一部分基因（例如 NKX2-1、GKN1、HNF4A 和 FOXA3）明显表达，而一些粘液相关基因（例如 SPDEF 和 FOXA2）在两种腺癌中都有表达。我们确定 HNF4A 诱导 MUC3A/B 和 TM4SF4，并且 HNF4A 拮抗剂 BI 6015 抑制 IMA 细胞的生长。使用与 COVID-19 相关的突变型 SPDEF，我们还确定 SPDEF 的完整 DNA 结合域是 SPDEF 介导的粘蛋白基因（MUC5AC、MUC5B 和 AGR2）诱导所必需的。此外，我们发现 XMU-MP-1（一种 SPDEF 抑制剂）可抑制 IMA 细胞的生长。这些结果表明，IMA 和 SRCC 含有异质肿瘤细胞类型，其中一些是可靶向的。

Invasive mucinous adenocarcinoma (IMA) comprises ∼5% of lung adenocarcinoma. There is no effective therapy for IMA when surgical resection is not possible. IMA is sometimes confused with adenocarcinoma with signet ring cell features (SRCC) pathologically since both adenocarcinomas feature tumor cells with abundant intracellular mucin. The molecular mechanisms by which such mucin-producing lung adenocarcinomas develop remain unknown.Using a Visium spatial transcriptomics approach, we analyzed IMA and compared it with SRCC patho-transcriptomically. Combining spatial transcriptomics data with in vitro studies using RNA-seq and ChIP-seq, we assessed downstream targets of transcription factors HNF4A and SPDEF that are highly expressed in IMA and/or SRCC.Spatial transcriptomics analysis indicated that there are 6 distinct cell clusters in IMA and SRCC. Notably, two clusters (C1 and C3) of mucinous tumor cells exist in both adenocarcinomas albeit at a different ratio. Importantly, a portion of genes (e.g., NKX2-1 , GKN1 , HNF4A and FOXA3 ) are distinctly expressed while some mucous-related genes (e.g., SPDEF and FOXA2 ) are expressed in both adenocarcinomas. We determined that HNF4A induces MUC3A/B and TM4SF4 and that BI 6015, an HNF4A antagonist, suppressed the growth of IMA cells. Using mutant SPDEF that is associated with COVID-19, we also determined that an intact DNA-binding domain of SPDEF is required for SPDEF-mediated induction of mucin genes ( MUC5AC , MUC5B and AGR2 ). Additionally, we found that XMU-MP-1, a SPDEF inhibitor, suppressed the growth of IMA cells.These results revealed that IMA and SRCC contain heterogenous tumor cell types, some of which are targetable.