High-dimensional deconstruction of pancreatic cancer identifies tumor microenvironmental and developmental stemness features that predict survival.
High-dimensional deconstruction of pancreatic cancer identifies tumor microenvironmental and developmental stemness features that predict survival.
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DOI：
10.1038/s41698-023-00455-z
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发表时间：
2023-10-19
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
--
作者：
已知许多细胞状态构成胰腺导管腺癌（PDAC）肿瘤微环境（TME）。然而，这些细胞状态的发育干细胞性和共现性仍然不清楚。在这里，我们对一组未经治疗的PDAC诊断时间内镜超声引导细针活检（EUS-FNB）样本（n = 25）进行了单细胞RNA测序（scRNA-seq）。然后，我们将这些样本与手术切除（n = 6）和公开可用的样本相结合，以增加统计功效（n = 80）。在注释成25种不同的细胞状态后，对细胞的发育干细胞性进行评分，并使用定制版本的Ecotyper工具来鉴定大量RNA-seq样品（n = 268）中共同出现的细胞状态的群落。我们发现了一个肿瘤微环境群落，包括侵袭性基底细胞样恶性细胞，肿瘤促进SPP 1+巨噬细胞和与预后特别差相关的肌纤维母细胞癌相关成纤维细胞。我们还发现了一个发育的干性连续体与生存的影响，是目前在恶性细胞和癌症相关的成纤维细胞（CAF）。我们进一步证明，使用标准治疗、诊断时间EUS-FNB标本进行高维分析预测生存率是可行的。总之，我们使用人体组织标本（包括诊断时间EUS-FNB样本）从PDAC的高维基因表达分析中确定了肿瘤微环境和发育干性特征。这些发现揭示了肿瘤微环境组成、CAF和恶性细胞干细胞性与患者生存之间的新联系，这可能会导致更好的前期风险分层和更个性化的前期临床决策。
Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n = 25). We then combined these samples with surgical resection (n = 6) and publicly available samples to increase statistical power (n = 80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness, and a customized version of the Ecotyper tool was used to identify communities of co-occurring cell states in bulk RNA-seq samples (n = 268). We discovered a tumor microenvironmental community comprised of aggressive basal-like malignant cells, tumor-promoting SPP1+ macrophages, and myofibroblastic cancer-associated fibroblasts associated with especially poor prognosis. We also found a developmental stemness continuum with implications for survival that is present in both malignant cells and cancer-associated fibroblasts (CAFs). We further demonstrated that high-dimensional analyses predictive of survival are feasible using standard-of-care, time-of-diagnosis EUS-FNB specimens. In summary, we identified tumor microenvironmental and developmental stemness characteristics from a high-dimensional gene expression analysis of PDAC using human tissue specimens, including time-of-diagnosis EUS-FNB samples. These reveal new connections between tumor microenvironmental composition, CAF and malignant cell stemness, and patient survival that could lead to better upfront risk stratification and more personalized upfront clinical decision-making.
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影响因子：
5.2
作者：
通讯作者：
--
影响因子：
24.5
作者：
Martinelli P;Carrillo-de Santa Pau E;Cox T;Sainz B Jr;Dusetti N;Greenhalf W;Rinaldi L;Costello E;Ghaneh P;Malats N;Büchler M;Pajic M;Biankin AV;Iovanna J;Neoptolemos J;Real FX
通讯作者：
Real FX
影响因子：
12.3
作者：
Lin W;Noel P;Borazanci EH;Lee J;Amini A;Han IW;Heo JS;Jameson GS;Fraser C;Steinbach M;Woo Y;Fong Y;Cridebring D;Von Hoff DD;Park JO;Han H
通讯作者：
Han H
影响因子：
30.8
作者：
Chan-Seng-Yue, Michelle;Kim, Jaeseung C.;Notta, Faiyaz
通讯作者：
Notta, Faiyaz
影响因子：
28.2
作者：
Elyada, Ela;Bolisetty, Mohan;Tuveson, David A.
通讯作者：
Tuveson, David A.