新辅助化疗治疗的卵巢癌组织中与残留病灶相关的蛋白质组学改变
Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues.
作者信息
Penick Emily R, Bateman Nicholas W, Rojas Christine, Magana Cuauhtemoc, Conrads Kelly, Zhou Ming, Hood Brian L, Wang Guisong, Parikh Niyati, Huang Ying, Darcy Kathleen M, Casablanca Yovanni, Mhawech-Fauceglia Paulette, Conrads Thomas P, Maxwell G Larry
机构信息
Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
出版信息
Clin Proteomics. 2022 Oct 4;19(1):35. doi: 10.1186/s12014-022-09372-y.
BACKGROUND
Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome for high-grade serous ovarian cancer (HGSOC) patients. Treatment of HGSOC patients with neoadjuvant chemotherapy, however, may select for tumor cells harboring alterations in hallmark cancer pathways including metastatic potential. This study assessed this hypothesis by performing proteomic analysis of matched, chemotherapy naïve and neoadjuvant chemotherapy (NACT)-treated HGSOC tumors obtained from patients who had suboptimal (R1, n = 6) versus optimal (R0, n = 14) debulking at interval debulking surgery (IDS).
METHODS
Tumor epithelium was harvested by laser microdissection from formalin-fixed, paraffin-embedded tissues from matched, pre- and post-NACT treated tumors for twenty HGSOC patients and analyzed by quantitative mass spectrometry-based proteomics.
RESULTS
Differential analysis of patient matched pre- and post-NACT treated tumors revealed proteins associated with cell survival and metabolic signaling to be significantly altered in post-NACT treated tumor cells. Comparison of pre-NACT treated tumors from suboptimal (R1) versus optimally (R0) debulked patients identified proteins associated with tumor cell viability and invasion signaling enriched in R1 patients. We identified five proteins altered between R1 and R0 patients in pre- NACT treated tumors that significantly correlated with PFS in an independent cohort of HGSOC patients, including Fermitin family homolog 2 (FERMT2), a protein elevated in R1 that correlated with disease progression in HGSOC patients (multivariate Cox HR = 1.65, Wald p = 0.022) and increased metastatic potential in solid-tumor malignancies.
CONCLUSIONS
This study identified distinct proteome profiles in patient matched pre- and post-NACT HGSOC tumors that correlate with NACT resistance and that may predict residual disease status at IDS that collectively warrant further pre-clinical investigation.
背景
对于高级别浆液性卵巢癌（HGSOC）患者，实现无残留疾病（R0）的最佳肿瘤细胞减灭与改善疾病预后相关。然而，对HGSOC患者进行新辅助化疗可能会选择出具有包括转移潜能在内的标志性癌症通路改变的肿瘤细胞。本研究通过对接受间隔减瘤手术（IDS）时减瘤效果欠佳（R1，n = 6）与减瘤效果最佳（R0，n = 14）的患者所获得的配对、未接受化疗和接受新辅助化疗（NACT）治疗的HGSOC肿瘤进行蛋白质组学分析，对这一假设进行了评估。
方法
通过激光显微切割从20例HGSOC患者配对的NACT治疗前和治疗后的福尔马林固定、石蜡包埋组织中获取肿瘤上皮，并通过基于定量质谱的蛋白质组学进行分析。
结果
对患者配对的NACT治疗前和治疗后的肿瘤进行差异分析发现，与细胞存活和代谢信号相关的蛋白质在NACT治疗后的肿瘤细胞中发生了显著改变。对减瘤效果欠佳（R1）与减瘤效果最佳（R0）的患者的NACT治疗前肿瘤进行比较，发现与肿瘤细胞活力和侵袭信号相关的蛋白质在R1患者中富集。我们在NACT治疗前的肿瘤中鉴定出R1和R0患者之间有5种蛋白质发生改变，这些蛋白质在一个独立的HGSOC患者队列中与无进展生存期显著相关，包括Fermitin家族同源物2（FERMT2），这是一种在R1中升高的蛋白质，与HGSOC患者的疾病进展相关（多变量Cox风险比 = 1.65，Wald p = 0.022），并增加实体瘤恶性肿瘤的转移潜能。
结论
本研究在患者配对的NACT治疗前和治疗后的HGSOC肿瘤中鉴定出了不同的蛋白质组图谱，这些图谱与NACT耐药相关，并且可能预测IDS时的残留疾病状态，这些结果共同值得进一步的临床前研究。
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