卵巢明細胞癌的異質性圖譜由單細胞空間轉錄體學揭示

Abstract

背景： 晚期卵巢透明細胞癌（OCCC）具有廣泛的轉移特性及複雜的細胞異質性。推動轉移的癌細胞亞群之空間組織與克隆演化過程目前仍不清楚。 方法： 本研究使用 CosMx SMI 1K 面板，對第 IV 期 OCCC 病患的三個福馬林固定石蠟包埋（FFPE）腫瘤樣本進行單細胞空間分析，分別來自卵巢、腹膜及結腸轉移部位。此外，我們也使用來自 4 位 OCCC 病患的 6 個 Visium 樣本作為獨立驗證隊列進行佐證。 結果： 共鑑定出 25 種單細胞類型，其中包含 9 種癌細胞亞群（標記為 a–i）。其中，癌細胞 f 在所有轉移部位中均可穩定觀察到，且根據軌跡分析推測為其他亞群的祖先克隆。癌細胞 f 的間質性分數顯著高於其他亞群（P < 0.001），並表現出形成微環境的趨勢。CellChat 分析顯示癌細胞 f 存在自分泌訊號活動，分別在腹膜與結腸部位富集 SPP1 與 LIFR 訊號通路。值得注意的是，轉移腫瘤呈現克隆瓶頸效應，僅有部分癌細胞亞群維持主導性的訊號活性與微環境適應能力。此現象伴隨纖維母細胞亞型的富集，以及在侵襲前緣中細胞互動動態從癌細胞－癌細胞轉為癌細胞－纖維母細胞的訊號交流，凸顯出支持轉移適應的空間性區隔溝通程式。 結論： 空間轉錄體學揭示出具有間質特徵與自分泌訊號活性的祖先癌細胞亞群，該亞群驅動轉移進程，並與 OCCC 預後不良相關。區域特異性的細胞通訊網絡與纖維母細胞重編程為調節微環境可塑性與侵襲行為的關鍵因子。

Background: Advanced ovarian clear cell carcinoma (OCCC) is characterized by extensive metastasis and complex cellular heterogeneity. The spatial organization and clonal evolution of cancer subpopulations driving metastasis remain poorly understood. Methods: The CosMx SMI 1K panel was used to profile the cellular landscape from three FFPE tumor samples of ovarian, peritoneal, and colonic metastatic sites in stage IV OCCC. Furthermore, validation was performed using 6 Visium samples from 4 OCCC patients as anindependent cohort. Results: A total of 25 single-cell types were identified, including 9 cancer cells (labelled a-i). Among them, the cancer f was consistently present across all metastatic sites and was inferred by trajectory analysis as the ancestral clone from which other subclones emerged. Cancer f cells exhibited a higher mesenchymal score compared to other cancer clones (P < 0.001) and showed niche-forming tendencies. CellChat analysis indicated autocrine signaling activities in cancer f cells, with SPP1 and LIFR pathways enriched in the peritoneal and colonic sites, respectively. Notably, metastatic tumors exhibited a clonal bottleneck effect, where only a subset of cancer clones maintained dominant signaling activity and niche adaptability. This was accompanied by enrichment of different fibroblast subtypes and a shift in interaction dynamics from cancer cancer to cancer-fibroblast signaling at invasion fronts, highlighting spatially compartmentalized communication programs that support metastatic adaptation. Conclusions: Spatial transcriptomics revealed an ancestral cancer subclone with mesenchymal features and autocrine signalling that drives metastatic progression and correlates with poor survival outcomes in OCCC. Region-specific communication networks and fibroblast reprogramming were key modulators of niche plasticity and invasion.