A 15-gene immune, stromal and proliferation gene signature that significantly associates with poor survival in patients with pancreatic ductal adenocarcinoma.
一种与胰腺导管腺癌患者生存率差显著相关的 15 基因免疫、间质和增殖基因标记。
- 作者列表："Kandimalla R","Tomihara H","Banwait JK","Yamamura K","Singh G","Baba H","Goel A
PURPOSE:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with dismal survival rates. Tumor microenvironment (TME), comprising of immune cells and cancer-associated fibroblasts, plays a key role in driving poor prognosis and resistance to chemotherapy. Herein, we aimed to identify a TME-associated, risk-stratification gene biomarker signature in PDAC. EXPERIMENTAL DESIGN:The initial biomarker discovery was performed in The Cancer Genome Atlas (TCGA, n=163) transcriptomic data. This was followed by independent validation of the gene signature in The International Cancer Genome Consortium (ICGC, n=95), E-MTAB-6134 (n=288), and GSE71729 (n=123) datasets for predicting overall survival (OS), and for its ability to detect poor molecular subtypes. Clinical validation and nomogram establishment was undertaken by performing multivariate cox regression analysis. RESULTS:Our biomarker discovery effort identified a 15-gene immune, stromal and proliferation (ISP) gene signature that significantly associated with poor OS (HR: 3.90, 95% CI, 2.36-6.41, p<0.0001). This signature also robustly predicted survival in 3 independent validation cohorts ICGC (HR:2.63 [1.56-4.41], p<0.0001), E-MTAB-6134 (HR:1.53 [1.14-2.04], p=0.004), and GSE71729 (HR:2.33 [1.49-3.63], p<0.0001). Interestingly, the ISP signature also permitted identification of poor molecular PDAC subtypes with excellent accuracy in all 4 cohorts; TCGA (AUC=0.94), ICGC (AUC=0.91), E-MTAB-6134 (AUC=0.80), and GSE71729 (AUC=0.83). The ISP-derived high-risk patients exhibited significantly poor OS in a clinical validation cohort (n=119; HR:2.62 [1.50-4.56], p=0.0004). A nomogram was established which included the ISP, CA19-9, T and N-stage for eventual clinical translation. CONCLUSIONS:We report a novel gene signature for risk-stratification and robust identification of PDAC patients with poor molecular subtypes.
目的: 胰腺导管腺癌 (PDAC) 是一种存活率低的致命性疾病。由免疫细胞和肿瘤相关成纤维细胞组成的肿瘤微环境 (TME) 在驱动不良预后和化疗抵抗中起关键作用。在此，我们旨在鉴定 PDAC 中 TME 相关的风险分层基因生物标志物标记。 实验设计: 在癌症基因组图谱 (TCGA，n = 163) 转录组数据中进行了初步的生物标志物发现。随后，国际癌症基因组联盟 (ICGC，n = 95) 、 E-MTAB-6134 (n = 288) 和 GSE71729 (n = 123) 对基因特征进行了独立验证。用于预测总生存期 (OS) 及其检测不良分子亚型能力的数据集。通过进行多变量 cox 回归分析进行临床验证和列线图建立。 结果: 我们的生物标志物发现工作确定了一个与不良 OS 显著相关的 15 基因免疫、基质和增殖 (ISP) 基因标记 (HR: 3.90，95% CI，2.36-6.41, p<0.0001)。该签名还稳健地预测了 3 个独立验证队列 ICGC (HR:2.63 [1.56-4.41]，p<0.0001)，E-MTAB-6134 (HR:1.53 [1.14-2.04], p = 0.004) 和 GSE71729 (HR:2.33 [1.49-3.63]，p<0.0001)。有趣的是，ISP 签名还允许在所有 4 个队列中以极好的准确性识别较差的分子 PDAC 亚型; TCGA (AUC = 0.94)，ICGC (AUC = 0.91),e-MTAB-6134 (AUC = 0.80) 和 GSE71729 (AUC = 0.83)。在临床验证队列中，ISP 衍生的高危患者表现出显著较差的 OS (n = 119; HR:2.62 [1.50-4.56]，p = 0.0004)。建立了一个列线图，包括 ISP 、 CA19-9 、 T 和 N 阶段，最终用于临床翻译。 结论: 我们报道了一种新的基因标记，用于对分子亚型较差的 PDAC 患者进行风险分层和稳健鉴定。
METHODS::Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The TP53 gene product regulates cell growth, aging, and cancer. To determine the important targets of TP53 in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-TP53 or lacked WT-TP53. MIA-PaCa-2 cells have a TP53 mutation as well as mutant KRAS and represent a good in vitro model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-TP53; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-TP53 or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-TP53 compared to cells expressing mTP53. Results from in vivo studies using human PDAC specimens confirmed the in vitro results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined SERPINE1 as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target (SERPINE1) of the TP53/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.
METHODS::Background: SLC6A14 (ATB0,+), a Na+/Cl-coupled transporter for neutral/cationic amino acids, is overexpressed in many cancers; It has been investigated as a target for improved liposomal drug delivery to treat liver cancer.Research design and methods: Here we explored the mechanism of ATB0,+-mediated entry of such liposomes. As ATB0,+ is highly-expressed in pancreatic cancer, we also examined the therapeutic utility of ATB0,+-targeted liposomal drug delivery to treat this cancer.Results: The uptake of lysine-conjugated liposomes (LYS-LPs) was greater in ATB0,+-positive MCF7 cells. The uptake process consisted of two steps: binding and internalization. The binding of LYS-LPs to MCF7 cells was higher than that of bare liposomes, and the process was dependent on Na+ and Cl-, and inhibitable by ATB0,+ substrates or blocker. In contrast, the internalization step was independent of lysine. The cellular entry of LYS-LPs facilitated by ATB0,+ occurred via endocytosis with transient endosomal degradation of ATB0,+ protein with subsequent recovery. Moreover, LYS-LPs also enhanced the uptake and cytotoxicity of gemcitabine in these cells in an ATB0,+-dependent manner.Conclusions: We conclude that ATB0,+ could be exploited for targeted drug delivery in the form of lysine-conjugated liposomes and that the approach represents a novel strategy for enhanced pancreatic cancer therapy.
METHODS:PURPOSE:Pre-operative prediction of histological response to neoadjuvant therapy aids decisions regarding surgical management of borderline resectable pancreatic cancer (BRPC). We elucidate correlation between pre-/post-treatment whole-tumor apparent diffusion coefficient (ADC) value and rate of tumor cell destruction. We newly verify whether post-treatment ADC value at the site of vascular contact predicts R0 resectability of BRPC. METHODS:We prospectively reviewed 28 patients with BRPC who underwent diffusion-weighted magnetic resonance imaging before neoadjuvant chemotherapy and surgery. Correlation between the percentage of tumor cell destruction and various parameters was analyzed. Strong parameters were assessed for their ability to predict therapeutic histological response and R0 resectability. RESULTS:Pre-/post-treatment whole-tumor ADC value correlated with tumor cell destruction rate by all parameters (R = 0.630/0.714, P 50% was determined at 1.40 × 10-3 mm2/s. It predicts histological response with 100% sensitivity, 81% specificity, and 89% accuracy. It predicts R0 with 88% sensitivity, 70% specificity, and 75% accuracy. CONCLUSIONS:Post-treatment whole-tumor ADC value may be a predictor of R0 resectability in patients with BRPC. Tumor cell destruction rate is indicated by the difference between pre-/post-treatment ADC values. This difference is strongly affected by the pre-treatment ADC value. The cutoff value of ADC at the site of vascular contact could not discriminate R0 resectability.