LBPO.CL01 · 临床研究 · Late-Breaking

分化簇44变异体亚型9界定胰腺上皮内瘤变空间生态位中的癌症干细胞库

Cluster of differentiation 44 variant isoform 9 defines cancer stem cell reservoirs in pancreatic intraepithelial neoplastic spatial niches

编号 LB017 展板 17 时间 4/19 02:00–05:00 区域 Section 50 主讲 Xi Sun, BS

分会场 Late-Breaking Research: Clinical Research 1

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作者与单位 Authors & Affiliations

Xi Sun¹, Ugonna Ezuma-Igwe¹, Abigail G. Branch¹, Jiang Wang², Juanita L. Merchant³, Syed A. Ahmad⁴, Davendra Sohal⁵, Petros G. Nikolinankos⁶, James Griffin⁶, Yana Zavros¹

¹University of Georgia, Athens, GA,²Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH,³Division of Gastroenterology and Hepatology, College of Medicine, University of Arizona, Tucson, AZ,⁴Department of Surgery, Division of Surgical Oncology, University of Cincinnati, Cincinnati, OH,⁵Hematology and Medical Oncology, University of Cincinnati, Cincinnati, OH,⁶University Cancer and Blood Center, Athens, GA

摘要 Abstract

中文摘要

背景：胰腺腺泡-导管化生（ADM）是一种适应性过程，其中分化的腺泡细胞在慢性应激或损伤反应下获得导管样特征。虽然ADM是一种允许腺泡细胞再生的可逆细胞过程，但慢性炎症或损伤会导致胰腺上皮内瘤变（PanIN）的发展，PanIN是常先于胰腺导管腺癌（PDAC）的癌前病变。界定ADM的分子靶点可以阻止疾病的发生和进展，从而形成可转化为临床实践的预防策略。我们的研究团队已经识别出一个持续存在于PDAC肿瘤微环境中的癌症干细胞（CSC）群体，其表达分化簇（CD）44变异体9（CD44v9）。CD44v9是一个已知的治疗耐药标志物，但其在早期疾病发生中的作用和检测仍未明确。目的：将CD44v9+ CSC界定为ADM和PanIN癌前病变中的储库，其促成PDAC患者的疾病复发。方法：我们使用CosMx™全转录组空间分子成像（CosMx™ WTx SMI）和Orion™多重免疫荧光（MxIF），分析了PDAC患者在一线全身化疗和Whipple手术后收集的PDAC组织。为进一步探究CD44v9是否在ADM和PanIN病变中表达，我们分析了患者匹配的邻近癌组织中的感兴趣区域。结果：MxIF染色识别出共表达腺泡细胞标志物淀粉酶和CD44v9的细胞，以及表达CD44v9+和导管标志物CK19+但缺乏淀粉酶的细胞。与化生转变一致，共表达淀粉酶和CK19的细胞也呈CD44v9阳性。CosMx™ WTx SMI数据分析显示，在被识别为ADM的同一细胞群体中CD44和导管标志物CK19（KRT19）共表达。PanIN病变表现出CD44、MUC6、MUC5AC和MUC1的高度共表达。经MxIF空间匹配，同一CD44v9+ PanIN病变还表达衰老相关分泌型MIF和CEACAM基因。通过CellChat计算工具对细胞间通讯的分析显示，与PanIN空间生态位共表达的CD44v9 CSC与炎性癌相关成纤维细胞、髓源性抑制细胞及腺泡和导管细胞之间的相互作用数量和强度最高。表达最高的基因与调控细胞外基质重组、衰老和免疫抑制的通路相关。结论：这些发现支持以下假说，即CD44v9+ CSC可能起源于恶变前病变，反映了在原发和转移部位观察到的持续CD44表达。CD44v9+ CSC可能作为PDAC患者治疗耐药和疾病复发的储库。

查看英文原文 English abstract

Background: Pancreatic acinar-to-ductal metaplasia (ADM) is an adaptive process inwhich differentiated acinar cells acquire duct-like characteristics in response to chronicstress or injury. While ADM is a reversible cellular process allowing acinar cellregeneration, chronic inflammation or injury leads to the development of pancreaticintraepithelial neoplasia (PanIN) that are precancerous lesions often precedingpancreatic ductal adenocarcinoma (PDAC). Defining molecular targets of ADM canimpede the initiation and progression of disease leading to preventive strategies thatcould be translated to clinical practice. Our research team has identified a cancer stemcell (CSC) population that persists within the PDAC tumor microenvironment expressingCluster of Differentiation (CD) 44, variant 9 (CD44v9). A known marker of therapy-resistance, the role and detection of CD44v9 in early disease initiation remains undefined. Objective: To define CD44v9+ CSCs as reservoirs within ADM and PanIN precancerouslesions contributing to disease recurrence in patients with PDAC.Methods: Using CosMx ™ Whole Transcriptome Spatial Molecular Imaging (CosMx ™ WTx SMI) and Orion ™ Multiplex Immunofluorescence (MxIF), we analyzed PDAC tissuescollected after first line systemic chemotherapy and the Whipple surgical procedure frompatients with PDAC. To further investigate whether CD44v9 is expressed within ADM andPanIN lesions, we analyzed regions of interest in patient matched adjacent cancertissues. Results: MxIF staining identified cells co-expressing the acinar cell marker amylase andCD44v9, alongside CD44v9+ and ductal marker CK19+ cells lacking amylase. Consistentwith metaplastic transition cells co-expressing amylase and CK19 were also positive forCD44v9. Analysis of the CosMx ™ WTx SMI data showed the co-expression of CD44and ductal marker CK19 (KRT19) in the same cell populations identified as ADM. PanINlesions exhibited high co-expression of CD44, MUC6, MUC5AC and MUC1. Spatiallymatched by MxIF, the same CD44v9+ PanIN lesions also expressed senescent-associated secretory MIF and CEACAM genes. Analysis of cell-cell communication bythe CellChat computational tool revealed that CD44v9 CSCs expressed with PanINspatial niches had the highest number of interactions and strength with inflammatorycancer associated fibroblasts, myeloid derived suppressor cells and acinar and ductalcells. The highest expressing genes were associated with pathways regulatingextracellular matrix re-organization, senescence and immunosuppression. Conclusions: These findings support the hypothesis that CD44v9+ CSCs may arise inpre-malignant lesions, mirroring the persistent CD44 expression observed in primary andmetastatic sites. CD44v9+ CSCs may serve as reservoir for therapeutic resistance anddisease recurrence in patients with PDAC.

利益披露 Disclosure

X. Sun, None.. U. Ezuma-Igwe, None.. A. G. Branch, None.. J. Wang, None.. J. L. Merchant, None.. S. A. Ahmad, None.. D. Sohal, None.. P. G. Nikolinankos, None.. J. Griffin, None.. Y. Zavros, None.

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