Elangovan Ashuvinee, Bossart Emily A, Basudan Ahmed, Tasdemir Nilgun, Shah Osama Shiraz, Ding Kai, Meier Carolin, Heim Tanya, Neumann Carola, Attaran Shireen, Brown Lauren, Hooda Jagmohan, Miller Lori, Liu Tiantong, Puhalla Shannon L, Gurda Grzegorz, Lucas Peter C, McAuliffe Priscilla F, Atkinson Jennifer M, Lee Adrian V, Oesterreich Steffi
bioRxiv. 2023 Sep 17:2023.09.15.558023. doi: 10.1101/2023.09.15.558023.
Breast cancer is categorized by the molecular and histologic presentation of the tumor, with the major histologic subtypes being No Special Type (NST) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark pathognomonic loss of E-cadherin ( ). Few ILC cell line models are available to researchers. Here we report the successful establishment and characterization of a novel ILC cell line, WCRC-25, from a metastatic pleural effusion from a postmenopausal Caucasian woman with metastatic ILC. WCRC-25 is an ER-negative luminal epithelial ILC cell line with both luminal and Her2-like features. It exhibits anchorage independent growth and haptotactic migration towards Collagen I. Sequencing revealed a Q706* truncating mutation, together with mutations in and , which were also seen in a series of metastatic lesions from the patient. Copy number analyses revealed amplification and deletion of genes frequently altered in ILC while optical genome mapping revealed novel structural rearrangements. RNA-seq analysis comparing the primary tumor, metastases and the cell line revealed signatures for cell cycle progression and receptor tyrosine kinase signaling. To assess targetability, we treated WCRC-25 with AZD5363 and Alpelisib confirming WCRC-25 as susceptible to PI3K/AKT signaling inhibition as predicted by our RNA sequencing analysis. In conclusion, we report WCRC-25 as a novel ILC cell line with promise as a valuable research tool to advance our understanding of ILC and its therapeutic vulnerabilities.
The work was in part supported by a Susan G Komen Leadership Grant to SO (SAC160073) and NCI R01 CA252378 (SO/AVL). AVL and SO are Komen Scholars, Hillman Foundation Fellows and supported by BCRF. This project used the UPMC Hillman Cancer Center and Tissue and Research Pathology/Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. This research was also supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. Finally, partial support was provided by the Magee-Womens Research Institute and Foundation, The Shear Family Foundation, and The Metastatic Breast Cancer Network.
乳腺癌根据肿瘤的分子和组织学表现进行分类，主要组织学亚型为非特殊类型（NST）和浸润性小叶癌（ILC）。ILC的特征是以单个细胞排列的方式生长，细胞间缺乏黏附性，并伴有基质浸润，这归因于其标志性的E-钙黏蛋白（ ）的病理特征性缺失。可供研究人员使用的ILC细胞系模型很少。在此，我们报告了一种新型ILC细胞系WCRC-25的成功建立和特性描述，该细胞系源自一名绝经后患有转移性ILC的白种女性的转移性胸腔积液。WCRC-25是一种ER阴性的管腔上皮ILC细胞系，具有管腔和Her2样特征。它表现出不依赖贴壁生长以及对I型胶原蛋白的趋触性迁移。测序显示存在一个Q706*截断突变，以及 和 中的突变，这些突变在该患者的一系列转移病灶中也可见。拷贝数分析揭示了ILC中频繁改变的基因的扩增和缺失，而光学基因组图谱揭示了新的结构重排。对原发性肿瘤、转移灶和细胞系进行RNA测序分析，揭示了细胞周期进展和受体酪氨酸激酶信号传导的特征。为了评估靶向性，我们用AZD5363和Alpelisib处理WCRC-25，证实WCRC-25如我们的RNA测序分析所预测的那样对PI3K/AKT信号抑制敏感。总之，我们报告WCRC-25是一种新型ILC细胞系，有望成为推进我们对ILC及其治疗易感性理解的有价值的研究工具。
这项工作部分得到了苏珊·G·科门领导力奖授予SO（SAC160073）以及美国国立癌症研究所R01 CA252378（SO/AVL）的支持。AVL和SO是科门学者、希尔曼基金会研究员，并得到了乳腺癌研究基金会的支持。本项目使用了匹兹堡大学医学中心希尔曼癌症中心以及组织与研究病理学/匹兹堡生物样本核心共享资源，该资源部分由P30CA047904奖资助。这项研究还部分得到了匹兹堡大学研究计算中心（RRID:SCR_022735）通过提供的资源的支持。具体而言，这项工作使用了HTC集群，该集群由美国国立卫生研究院授予编号S10OD028483的奖项资助。最后，部分支持由梅杰妇女研究所和基金会、希尔家族基金会以及转移性乳腺癌网络提供。
