El Baba Ranim, Pasquereau Sébastien, Haidar Ahmad Sandy, Diab-Assaf Mona, Herbein Georges
Pathogens & Inflammation/EPILAB Laboratory, EA 4266, Université de Franche-Comté, Université Bourgogne Franche-Comté (UBFC), 25030 Besançon, France.
Molecular Cancer and Pharmaceutical Biology Laboratory, Lebanese University, Beirut 1500, Lebanon.
Cancers (Basel). 2022 Sep 1;14(17):4271. doi: 10.3390/cancers14174271.
Human cytomegalovirus (HCMV) oncomodulation, molecular mechanisms, and ability to support polyploid giant cancer cells (PGCCs) generation might underscore its contribution to oncogenesis, especially breast cancers. The heterogeneity of strains can be linked to distinct properties influencing the virus-transforming potential, cancer types induced, and patient's clinical outcomes.
We evaluated the transforming potential in vitro and assessed the acquired cellular phenotype, genetic and molecular features, and stimulation of stemness of HCMV strains, B544 and B693, isolated from EZH2Myc triple-negative breast cancer (TNBC) biopsies. Therapeutic response assessment after paclitaxel (PTX) and ganciclovir (GCV) treatment was conducted in addition to the molecular characterization of the tumor microenvironment (TME).
HCMV-B544 and B693 transformed human mammary epithelial cells (HMECs). We detected multinucleated and lipid droplet-filled PGCCs harboring HCMV. Colony formation was detected and Myc was overexpressed in CMV-Transformed-HMECs (CTH cells). CTH-B544 and B693 stimulated stemness and established an epithelial/mesenchymal hybrid state. HCMV-IE1 was detected in CTH long-term cultures indicating a sustained viral replication. Biopsy B693 unveiled a tumor signature predicting a poor prognosis. CTH-B544 cells were shown to be more sensitive to PTX/GCV therapy.
The oncogenic and stemness signatures of HCMV strains accentuate the oncogenic potential of HCMV in breast cancer progression thereby leading the way for targeted therapies and innovative clinical interventions that will improve the overall survival of breast cancer patients.
人巨细胞病毒（HCMV）的促癌作用、分子机制以及支持多倍体巨癌细胞（PGCCs）生成的能力可能突出了其在肿瘤发生过程中的作用，尤其是在乳腺癌中。病毒株的异质性可能与影响病毒转化潜力、诱发的癌症类型以及患者临床结局的不同特性有关。
我们评估了从EZH2Myc三阴性乳腺癌（TNBC）活检组织中分离出的HCMV毒株B544和B693的体外转化潜力，并评估了获得的细胞表型、遗传和分子特征以及对干性的刺激作用。除了对肿瘤微环境（TME）进行分子特征分析外，还进行了紫杉醇（PTX）和更昔洛韦（GCV）治疗后的治疗反应评估。
HCMV-B544和B693转化了人乳腺上皮细胞（HMECs）。我们检测到含有HCMV的多核且充满脂滴的PGCCs。在CMV转化的HMECs（CTH细胞）中检测到集落形成且Myc过表达。CTH-B544和B693刺激干性并建立上皮/间充质混合状态。在CTH长期培养物中检测到HCMV-IE1，表明病毒持续复制。活检B693揭示了一个预测预后不良的肿瘤特征。CTH-B544细胞对PTX/GCV治疗更敏感。
HCMV毒株的致癌和干性特征突出了HCMV在乳腺癌进展中的致癌潜力，从而为靶向治疗和创新临床干预开辟了道路，这将提高乳腺癌患者的总体生存率。
