Purpose: To establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance. Experimental Design: We identified high expression of HMGA2 in basal PDAC cells in a scRNAseq Atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classical marker GATA6, in a cohort of 580 PDAC samples with multiplex immunohistochemistry. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNAseq databases. Results: We found that expression of HMGA2, but not previously described basal markers CK5 or CK17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n=94, median survival=11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n=198, median survival=21.7 months post-surgery). HMGA2 was also prognostic for overall survival in RNA sequencing from an independent cohort. Conclusions: IHC stratification of primary tumors by HMGA2 and GATA6 status in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.

中文翻译：

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HMGA2 表达可预测胰腺导管腺癌的亚型、生存率和治疗结局


目的：确立 HMGA2 作为胰腺导管腺癌 （PDAC） 基底样疾病的标志物，并探索其作为预后和治疗耐药的生物标志物。实验设计： 我们在 172 例患者样本的 scRNAseq 图谱中鉴定了 HMGA2 在基础 PDAC 细胞中的高表达。然后，我们用多重免疫组织化学分析了 580 例 PDAC 样本队列中的 HMGA2 表达以及经典标志物 GATA6 的表达。我们进一步补充了这些数据，增加了 30 个不同的患者样本和多个独立的单细胞 RNAseq 数据库。结果： 我们发现 HMGA2 的表达，但之前未描述的基础标志物 CK5 或 CK17 的表达，预测了我们队列的总生存期。结合 HMGA2 和 GATA6 状态可以确定两个关键研究组：HMGA2+/GATA6- 队列生存率较差，肿瘤浸润性 CD8+ T 细胞低，FAP+ 成纤维细胞增加，对基于吉西他滨的化疗反应较差（n=94，术后中位生存期 = 11.2 个月）;以及一个 HMGA2-/GATA6 + 队列，以吉西他滨为基础的化疗提高了生存率，增加了 CD8 + T 细胞浸润，减少了 FAP+ 成纤维细胞，并提高了生存率 （n=198，术后中位生存期 = 21.7 个月）。HMGA2 在独立队列的 RNA 测序中也预后结论： 胰腺癌中 HMGA2 和 GATA6 状态对原发肿瘤进行 IHC 分层与差异结局、化疗后生存率和肿瘤微环境相关。作为基底病的核标志物，HMGA2 补充 GATA6 以识别 PDAC 中的疾病亚型。