Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Australian Centre for Blood Diseases, Central Clinical School, Monash University and Alfred Health, Melbourne, Victoria, Australia.
Clin Cancer Res. 2023 May 15;29(10):1969-1983. doi: 10.1158/1078-0432.CCR-22-2254.
We recently reported that the transcription factor NFATC4, in response to chemotherapy, drives cellular quiescence to increase ovarian cancer chemoresistance. The goal of this work was to better understand the mechanisms of NFATC4-driven ovarian cancer chemoresistance.
We used RNA sequencing to identify NFATC4-mediated differential gene expression. CRISPR-Cas9 and FST (follistatin)-neutralizing antibodies were used to assess impact of loss of FST function on cell proliferation and chemoresistance. ELISA was used to quantify FST induction in patient samples and in vitro in response to chemotherapy.
We found that NFATC4 upregulates FST mRNA and protein expression predominantly in quiescent cells and FST is further upregulated following chemotherapy treatment. FST acts in at least a paracrine manner to induce a p-ATF2-dependent quiescent phenotype and chemoresistance in non-quiescent cells. Consistent with this, CRISPR knockout (KO) of FST in ovarian cancer cells or antibody-mediated neutralization of FST sensitizes ovarian cancer cells to chemotherapy treatment. Similarly, CRISPR KO of FST in tumors increased chemotherapy-mediated tumor eradication in an otherwise chemotherapy-resistant tumor model. Suggesting a role for FST in chemoresistance in patients, FST protein in the abdominal fluid of patients with ovarian cancer significantly increases within 24 hours of chemotherapy exposure. FST levels decline to baseline levels in patients no longer receiving chemotherapy with no evidence of disease. Furthermore, elevated FST expression in patient tumors is correlated with poor progression-free, post-progression-free, and overall survival.
FST is a novel therapeutic target to improve ovarian cancer response to chemotherapy and potentially reduce recurrence rates.
我们最近报道称，转录因子 NFATC4 在化疗作用下，驱动细胞静止以增加卵巢癌的化疗耐药性。本研究的目的是更好地了解 NFATC4 驱动的卵巢癌化疗耐药的机制。
我们使用 RNA 测序来鉴定 NFATC4 介导的差异基因表达。使用 CRISPR-Cas9 和 FST（卵泡抑素）中和抗体来评估 FST 功能丧失对细胞增殖和化疗耐药性的影响。ELISA 用于定量患者样本和体外化疗后 FST 的诱导。
我们发现 NFATC4 主要在静止细胞中上调 FST mRNA 和蛋白表达，并且在化疗后进一步上调。FST 至少以旁分泌的方式作用，在非静止细胞中诱导依赖 p-ATF2 的静止表型和化疗耐药性。与此一致的是，卵巢癌细胞中 FST 的 CRISPR 敲除（KO）或 FST 的抗体中和使卵巢癌细胞对化疗更敏感。同样，在原本对化疗耐药的肿瘤模型中，FST 的 CRISPR KO 增加了化疗介导的肿瘤清除。提示 FST 在患者化疗耐药中的作用，卵巢癌患者的腹腔液中 FST 蛋白在化疗暴露后 24 小时内显著增加。在不再接受化疗且无疾病证据的患者中，FST 水平下降至基线水平。此外，患者肿瘤中 FST 的高表达与无进展生存期、进展后无生存期和总生存期较差相关。
FST 是一种新的治疗靶点，可提高卵巢癌对化疗的反应，降低复发率。
