PO.TB10.04 · 肿瘤生物学
原发性和转移性前列腺肿瘤的全面图谱分析揭示与雄激素耐药相关的独特肿瘤和成纤维细胞状态
Comprehensive profiling of primary and metastatic prostate tumors reveals distinct tumor and fibroblast cell states associated with androgen resistance
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中文摘要
前列腺癌需要持续逃避免疫监视，但在从雄激素敏感向耐药和转移转变过程中这种逃逸的潜在机制仍不完全清楚。雄激素剥夺治疗（ADT）——作为治疗基石——诱导肿瘤细胞凋亡，但也重塑肿瘤微环境（TME）。我们组建了一个来自哥伦比亚大学和纪念斯隆凯特琳癌症中心治疗的68例患者、超过800,000个细胞的单细胞RNA-seq图谱。该资源包括33例原发性肿瘤（16例初治、17例ADT后），并标注了PSA复发时间，以及31例转移灶，其中包括14例去势敏感性肿瘤（CSPC）、17例去势抵抗性肿瘤（CRPC）和4例神经内分泌肿瘤（NEPC）的纵向ADT前后数据。该数据集涵盖了前列腺癌疾病进展的全谱。使用ARACNe和VIPER推断转录调控和信号蛋白的活性，我们检测到保守的细胞状态程序，同时最大限度地减少批次效应。出现了几个显著特征。免疫浸润——包括淋巴系和髓系——在CSPC转移灶中显著高于原发性或CRPC肿瘤，并在ADT后进一步增加。T细胞在原发性肿瘤中约占细胞的15%，而在初治CSPC中占30%（ADT后40%），在CRPC中降至13%，在NEPC中低于1%（p<1e-32），与最初“热”的CSPC TME一致，该微环境随疾病进展逐渐排斥T细胞。在约350,000个上皮/肿瘤细胞中，轨迹分析揭示了从正常上皮分化出的两条分化途径。途径1——在原发性肿瘤中占主导——表现出雄激素受体（AR）活性，具有三种亚表型（T1-T3）：T1为原发性肿瘤所特有；T2为原发性和CSPC共有；T3局限于CRPC，具有高ERG表达和非常强的AR活性。途径2（簇T4-T6）存在于NEPC和部分CRPC中，缺乏AR活性，并显示SOX2、FOXA2、PRKD1。这些侵袭性状态一致地过表达AURKA、RET和TOP2A，提示可用于联合治疗的可成药靶点。我们进一步定义了五种癌症相关成纤维细胞（CAF）亚型。CAF1-3与晚期、耐药性疾病相关——在NEPC中比CRPC更富集（占CAF的25% vs 18%），在CRPC中比CSPC更富集（18% vs 11%）——而CAF4-5在原发性肿瘤中占主导。我们鉴定了将CAF1-3与T4-T6肿瘤状态相联系的可成药蛋白和受体-配体相互作用；体内扰动实验正在进行中。该图谱提供了描绘前列腺癌进展中肿瘤和免疫生态系统的资源。它突出了支撑免疫逃逸和ADT耐药的主调控（MR）程序以及基质-肿瘤-免疫相互作用，为侵袭性疾病提供了可操作的靶点和联合治疗假设。
查看英文原文 English abstract
Prostate cancer requires continual escape from immune surveillance, but mechanisms underlying this escape in the transition from androgen sensitivity to resistance and metastasis remain incompletely understood. Androgen-deprivation therapy (ADT)-the treatment backbone-induces tumor cell apoptosis but also remodels the tumor microenvironment (TME). We have assembled a single-cell RNA-seq atlas from >800,000 cells across 68 patients treated at Columbia University and Memorial Sloan Kettering. The resource includes 33 primary tumors (16 treatment-naïve, 17 post-ADT) annotated with time to PSA recurrence, and 31 metastases, including longitudinal pre- and post-ADT data in 14 castration-sensitive tumors (CSPC), 17 castration-resistant tumors (CRPC), and 4 neuroendocrine tumors (NEPC). This dataset spans the spectrum of prostate cancer disease progression.Using ARACNe and VIPER to infer activity of transcriptional regulatory and signaling proteins, we detect conserved cell state programs while minimizing batch effects. Several significant features emerged. Immune infiltration-both lymphoid and myeloid-is significantly higher in CSPC metastases than in primary or CRPC tumors and increases further after ADT. T cells constitute ~15% of cells in primary tumors versus 30% in treatment-naive CSPC (40% post-ADT), falling to 13% in CRPC and <1% in NEPC (p<1e-32), consistent with an initially "hot" CSPC TME that progressively excludes T cells with disease progression.Among ~350,000 epithelial/tumor cells, trajectory analysis reveals two differentiation pathways from normal epithelium. Pathway 1-dominant in primary tumors-shows androgen receptor (AR) activity with three sub-phenotypes (T1-T3): T1 exclusive to primary tumors; T2 shared by primary and CSPC; and T3 restricted to CRPC, with high ERG expression, and very strong AR activity. Pathway 2 (clusters T4-T6), present in NEPC and a subset of CRPC, lacks AR activity and displays SOX2, FOXA2, PRKD1. These aggressive states uniformly overexpress AURKA, RET, and TOP2A, suggesting druggable targets for combination therapy.We further define five cancer-associated fibroblast (CAF) subtypes. CAF1-3 track with advanced, treatment-resistant disease-enriched in NEPC versus CRPC (25% vs 18% of CAFs) and in CRPC versus CSPC (18% vs 11%)-while CAF4-5 predominate in primary tumors. We identify druggable proteins and receptor-ligand interactions linking CAF1-3 with T4-T6 tumor states; in vivo perturbations are underway.This atlas provides a resource profiling tumor and immune ecosystems across prostate cancer progression. It highlights MR programs and stromal-tumor-immune interactions that underlie immune evasion and ADT resistance, yielding actionable targets and combination-therapy hypotheses for aggressive disease.
利益披露 Disclosure
A. Obradovic, None..
K. Yoo, None..
P. McCann, None..
C. R. Ager, None..
M. C. Dallos, None..
S. Zaidi, None.