Kramer Maranda, Criswell Allyson, Marzette Kamari, Cutcliffe Emerson, Sewell-Loftin Mary Kathryn
Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Biomedical Sciences Program, Department of Clinical and Diagnostic Sciences, School of Health Professions, University of Alabama at Birmingham, USA.
Mechanobiol Med. 2024 Sep 2;2(4):100094. doi: 10.1016/j.mbm.2024.100094. eCollection 2024 Dec.
The ovarian tumor microenvironment plays a critical yet is poorly understood role in the regulation of cancer cell behaviors including proliferation, migration, and response to chemotherapy treatments. Ovarian cancer is the deadliest gynecological cancer, due to diagnosis at late stages of the disease and increased resistance to chemotherapies for recurrent disease. Understanding how the tumor microenvironment (TME) interacts with biomechanical forces to drive changes to ovarian cancer cell behaviors could elucidate novel treatment strategies for this patient population. Additionally, limitations in current preclinical models of the ovarian TME do not permit investigation of crosstalk between signaling pathways and mechanical forces. Our study focused on uncovering how strains and hyaluronic acid (HA) interact to signal through the CD44 receptor to alter ovarian cancer cell growth, migration, and response to a commonly used chemotherapy, paclitaxel. Using an advanced 3D model, we were able to identify how interactions of strain and HA as in the TME synergistically drive enhanced proliferation and migration in an ovarian tumor model line, while decreasing response to paclitaxel treatment. This study demonstrates the importance of elucidating how the mechanical forces present in the ovarian TME drive disease progression and response to treatment.
卵巢肿瘤微环境在调控癌细胞行为（包括增殖、迁移以及对化疗的反应）方面发挥着关键作用，但人们对其了解甚少。卵巢癌是最致命的妇科癌症，这是由于该疾病在晚期才被诊断出来，且复发性疾病对化疗的耐药性增加。了解肿瘤微环境（TME）如何与生物力学力相互作用以驱动卵巢癌细胞行为的变化，可能会为这一患者群体阐明新的治疗策略。此外，当前卵巢TME临床前模型的局限性不允许对信号通路与机械力之间的相互作用进行研究。我们的研究重点是揭示应变和透明质酸（HA）如何相互作用，通过CD44受体发出信号，从而改变卵巢癌细胞的生长、迁移以及对常用化疗药物紫杉醇的反应。使用先进的三维模型，我们能够确定TME中应变与HA的相互作用如何在卵巢肿瘤模型系中协同驱动增殖和迁移增强，同时降低对紫杉醇治疗的反应。这项研究证明了阐明卵巢TME中存在的机械力如何驱动疾病进展和对治疗的反应的重要性。
