PURPOSE Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard of care treatments and have significantly worse overall survival (OS) compared to patients with classical subtype enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner. EXPERIMENTAL DESIGN We compiled a single cell RNA sequencing (scRNAseq) atlas of the human pancreas with 229 patient samples, aggregated from publicly available raw data. We mapped cell-type specific scRNAseq gene signatures in bulk RNAseq (n=744) and spatial transcriptomics (ST) (n=22) and performed validation using multiplex immunostaining. RESULTS Analysis of tumor cells from our scRNAseq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse OS in bulk RNAseq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in non-dissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer associated fibroblasts (CAFs) with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in PDAC tumor microenvironment. CONCLUSIONS We show that our scRNAseq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ CAFs and basal tumor cells that could be explored for future targeted therapies.

中文翻译：

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人胰腺癌单细胞图谱揭示了 CXCL10 + 成纤维细胞与基底亚型肿瘤细胞的关联。


目的 与经典亚型富集肿瘤患者相比，富含基底样分子亚型的肿瘤的胰腺导管腺癌 （PDAC） 患者对标准护理治疗的抵抗力增强，并且总生存期 （OS） 显著差。开发基因组资源非常重要，能够以统计学严格的方式识别新的推定靶标。实验设计 我们编制了一份包含 229 个患者样本的人类胰腺单细胞 RNA 测序 （scRNAseq） 图谱，这些样本是从公开可用的原始数据汇总而来的。我们在批量 RNAseq （n=744） 和空间转录组学 （ST） （n=22） 中定位了细胞类型特异性 scRNAseq 基因特征，并使用多重免疫染色进行了验证。结果 来自我们的 scRNAseq 图谱的肿瘤细胞分析揭示了 9 个不同的群体，其中两个与基础亚型一致，与大量 RNAseq 中较差的 OS 相关。反卷积确定其中一个基底群体是未解离的 ST 组织以及体外肿瘤细胞和患者来源的类器官系中的主要肿瘤亚型。我们发现了 CXCL10 + 癌症相关成纤维细胞 （CAF） 与基底肿瘤细胞的新富集和空间关联。我们发现，除了免疫细胞外，导管细胞还表达 CXCL10 受体 CXCR3，表明这些细胞类型在 PDAC 肿瘤微环境中之间存在关系。结论我们表明，我们的 scRNAseq 图谱 （700,000 个细胞） 与 ST 数据整合，具有更高的统计能力，是一种强大的资源，允许扩展 PDAC 中当前的亚型范式。我们发现了一种以 CXCL10 + CAFs 和基底肿瘤细胞为标志的新型信号生态位，可以探索未来的靶向治疗。