Ayala Carlos, Sathe Anuja, Bai Xiangqi, Grimes Susan M, Shen Jeanne, Poultsides George A, Lee Byrne, Ji Hanlee P
Division of Surgical Oncology, Department of Surgery, Stanford University, Stanford, CA, United States.
Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.
Front Genet. 2025 Feb 13;16:1536982. doi: 10.3389/fgene.2025.1536982. eCollection 2025.
Appendiceal mucinous neoplasms (AMN) are rare tumors of the gastrointestinal tract. They metastasize with widespread abdominal dissemination leading to pseudomyxoma peritonei (PMP), a disease with poor prognosis. There are many unknowns about the cellular features of origin, differentiation and progression of AMN and PMP.
We characterized AMNs, PMPs and matched normal tissues using single-cell RNA-sequencing. We validated our findings with immunohistochemistry, mass spectrometry on malignant ascites from PMP patients and gene expression data from an independent set of PMP tumors.
We identified previously undescribed cellular features and heterogeneity in AMN and PMP tumors. There were gene expression signatures specific to the tumor epithelial cells among AMN and PMP. These signatures included genes indicative of goblet cell differentiation and elevated mucin gene expression. Metastatic PMP cells had a distinct gene expression signature with increased lipid metabolism, inflammatory, JAK-STAT and RAS signaling pathway among others. We observed clonal heterogeneity in a single PMP tumor as well as PMP metastases from the same patient.
Our study defined tumor cell gene signatures of AMN and PMP, successfully overcoming challenges of low cellularity and mucinous composition of these tumors. These gene expression signatures provide insights on tumor origin and differentiation, together with the identification of novel treatment targets. The heterogeneity observed within an individual tumor and between different tumors from the same patient, represents a potential source of treatment resistance.
阑尾黏液性肿瘤（AMN）是胃肠道的罕见肿瘤。它们通过广泛的腹腔播散发生转移，导致腹膜假黏液瘤（PMP），这是一种预后不良的疾病。关于AMN和PMP的起源、分化及进展的细胞特征，仍有许多未知之处。
我们使用单细胞RNA测序对AMN、PMP及匹配的正常组织进行了特征分析。我们通过免疫组织化学、对PMP患者恶性腹水的质谱分析以及来自一组独立PMP肿瘤的基因表达数据对我们的发现进行了验证。
我们在AMN和PMP肿瘤中发现了先前未描述的细胞特征和异质性。AMN和PMP中的肿瘤上皮细胞有特定的基因表达特征。这些特征包括指示杯状细胞分化和黏蛋白基因表达升高的基因。转移性PMP细胞有独特的基因表达特征，脂质代谢、炎症、JAK-STAT和RAS信号通路等增加。我们在单个PMP肿瘤以及同一患者的PMP转移灶中观察到了克隆异质性。
我们的研究定义了AMN和PMP的肿瘤细胞基因特征，成功克服了这些肿瘤细胞数量少和黏液成分带来的挑战。这些基因表达特征为肿瘤起源和分化提供了见解，同时也确定了新的治疗靶点。在单个肿瘤内以及同一患者的不同肿瘤之间观察到的异质性，是潜在的治疗抵抗来源。
