LBPO.CL01 · 临床研究 · Late-Breaking

绘制CD44v9的时空动态图谱揭示了胰腺癌中一个衰老的细胞治疗耐药性生态位

Mapping the spatiotemporal dynamics of CD44v9 reveals a senescent cell therapy-resistant niche in pancreatic cancer

编号 LB009 展板 9 时间 4/19 02:00–05:00 区域 Section 50 主讲 ugonna ezuma-igwe

分会场 Late-Breaking Research: Clinical Research 1

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作者与单位 Authors & Affiliations

Ugonna Ezuma-Igwe¹, Xi Sun¹, Abigail G. Branch¹, Sangmin Kim², Rohan Kanakamedala², Payton Stevens³, Jiang Wang⁴, Syed A. Ahmad⁵, Davendra Sohal⁶, Petros G. Nikolinakos⁷, James Griffin⁷, Yana Zavros¹

¹University of Georgia School of Medicine, Athens, GA,²Medical College of Georgia, Augusta University/University of Georgia Medical Partnership, Athens, GA,³Miami University, Department of Biological Sciences, Oxford, OH,⁴Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH,⁵Department of Surgery, Division of Surgical Oncology, University of Cincinnati, Cincinnati, OH,⁶Hematology and Medical Oncology, University of Cincinnati, Cincinnati, OH,⁷University Cancer and Blood Center, Athens, GA

摘要 Abstract

中文摘要

背景：尽管在癌症治疗方面已有数十年的研究和进展，胰腺导管腺癌（PDAC）仍是最致命的恶性肿瘤之一，其治疗应答有限，且具有高度纤维化和免疫抑制性的肿瘤微环境（TME）。细胞黏附分子分化簇（CD）44跨膜糖蛋白（CD44）的选择性mRNA剪接产生变体异构体（CD44v）CD44v9。CD44v9稳定胱氨酸/谷氨酸反向转运体SLC7A11，增强谷胱甘肽合成以缓冲活性氧和化疗耐药。尽管CD44v9是已知的癌症干细胞（CSC）标志物并与化疗耐药相关，但尚未完成在疾病进展背景下对CD44v9表达的全面时空分析。目的：将CD44v9识别为一个潜在的治疗靶点，以及化疗耐药、疾病进展和转移的驱动因素。方法：使用RareCyte Orion™多重免疫荧光（MxIF）和CosMx™全转录组空间分子成像仪（CosMx™ WTX SMI），利用PDAC患者在标准治疗（SOC）化疗前后的纵向肿瘤组织，测量CD44v9表达的时空动态。MxIF图像被整理为Minerva Stories（https://uga-som-imtm.github.io/170-8T-211-09T/）以供交互式数据浏览。使用由匹配的纵向组织样本生成的、含有癌症相关成纤维细胞（CAF）的患者来源类器官（PDO），以识别靶向CD44v9的治疗获益。四种新型CD44v9导向的抗体-药物偶联物（CD44v9-ADC；Abzena），每种均设计用于靶向衰老或抗氧化防御，单独测试并与标准治疗（SOC）化疗药物联合测试。结果：对纵向采集的肿瘤组织进行CosMx™ WTX SMI显示，细胞生态位内CD44阳性细胞的表达增加。对匹配组织切片进行的MxIF揭示了在同一个空间上识别的CD44阳性细胞群体内存在CD44v9表达。CD44v9+ CSC表现出衰老相关分泌表型，MIF和CEACAM基因高表达，并驻留于富含癌症相关成纤维细胞、施万细胞和免疫抑制性细胞特征的生态位内。用CD44v9-ADC联合治疗PDO导致其对SOC诱导的肿瘤细胞死亡敏感化，这通过高内涵共聚焦显微镜以核不规则指数、碘化丙啶摄取和周长减小来测量。结论：CD44v9的表达标志着一个在SOC治疗后仍持续存在于患者PDAC TME中的CSC群体。携带衰老溶解性和抗氧化防御抑制性载荷的CD44v9导向ADC，是一种潜在的治疗方法，可用于预防疾病进展、复发和转移。

查看英文原文 English abstract

Background: Despite decades of research and advances in cancer therapeutics, pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with limited therapeutic response and a profoundly fibrotic and immunosuppressive tumor microenvironment (TME). Alternative mRNA splicing of cell adhesion molecule Cluster of Differentiation (CD) 44 transmembrane glycoprotein (CD44) generates variant isoform (CD44v) CD44v9. CD44v9 stabilizes the cystine/glutamate antiporter SLC7A11, enhancing glutathione synthesis to buffer reactive oxygen species and chemotherapeutic resistance. Although CD44v9 is a known cancer stem cell (CSC) marker and has been linked to chemotherapy resistance, a comprehensive spatiotemporal analysis of CD44v9 expression in the context of disease progression has not been completed. Objective: To identify CD44v9 as a potential therapeutic target and driver of chemotherapy resistance, progression of disease, and metastasis. Methods: The spatiotemporal dynamics of CD44v9 expression were measured using PDAC patient longitudinal tumor tissues pre- and post-SOC chemotherapy using the Rarecyte Orion ™ Multiplex Immunofluorescence (MxIF) and CosMx ™ Whole Transcriptome Spatial Molecular Imager (CosMx ™ WTX SMI). MxIF images were curated into Minerva Stories (https://uga-som-imtm.github.io/170-8T-211-09T/) for interactive data. Patient-derived organoids (PDO) harboring cancer associated fibroblasts (CAFs) generated from matched longitudinal tissue samples were used to identify the therapeutic benefit of targeting CD44v9. Four novel CD44v9-directed antibody-drug conjugates (CD44v9-ADCs; Abzena), each designed to target senescence or antioxidant defense were tested alone and in combination with standard-of-care (SOC) chemotherapeutic drugs. Results: CosMx ™ WTX SMI of longitudinal collected tumor tissues showed an increased expression of CD44 positive cells within cell niches. MxIF of matched tissue sections revealed expression of CD44v9 within the same CD44 positive spatially identified cell population. CD44v9+ CSCs exhibited a senescent-associated secretory phenotype with high expression of MIF and CEACAM genes, and resided within niches dense with cancer associated fibroblasts, Schwann cells, and an immune suppressive cells signature. Combination treatment of PDOs with CD44v9-ADCs resulted in sensitization to SOC-induced tumor cell death, as measured by high-content confocal microscopy by nuclear irregularity index, propidium iodide uptake and decreased circumference. Conclusion: The expression of CD44v9 marks a CSC population that persists within the patient PDAC TME post-SOC. CD44v9-directed ADCs, carrying senolytic and antioxidant defense-inhibiting payloads, are a potential therapeutic approach to prevent disease progression, recurrence, and metastasis.

利益披露 Disclosure

U. Ezuma-Igwe, None.. X. Sun, None.. A. G. Branch, None.. S. Kim, None.. R. Kanakamedala, None.. P. Stevens, None.. J. Wang, None.. S. A. Ahmad, None.. D. Sohal, None.. P. G. Nikolinakos, None.. J. Griffin, None.. Y. Zavros, None.

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