Molecular Profiling of Pancreatic Cancer

胰腺癌研究的主要挑战之一是获得手术切除患者的临床样本，并提供完整的人口统计学和临床病理信息。在我们持续的努力中，我们已经成功地从美国和国外的病例中建立了多个切除的胰腺癌样本队列。这包括一项新批准的研究方案，从大巴尔的摩地区的500例PDAC病例中收集肿瘤和/或血液样本，由我担任主要研究员。这些收藏品将是我们胰腺癌项目的宝贵财富。我们的前期基因表达谱研究结果显示，在两个独立的PDAC队列中，肿瘤中DPEP1（二肽酶1）的低表达与较差的生存率相关，并且与分期和切除边缘状态无关（Zhang等人，PLoS One, 2012）。在两个队列中，与来自同一患者的邻近非肿瘤胰腺相比，肿瘤中的DPEP1表达显著降低。胰腺癌细胞系中DPEP1的过表达抑制了细胞的迁移和侵袭，并增加了对吉西他滨的敏感性，吉西他滨是治疗胰腺癌的一线药物。我们还发现DPEP1受EGF/MEK/MAPK通路的调控，MEK1/2抑制剂在体外增强了DPEP1的表达。鉴于这些发现，我们提出通过新方法重新表达DPEP1可能有助于PDAC的治疗，提高患者的生存率。目前，我们正在体内测试DPEP1抑制肿瘤进展的假设。在我们继续研究与疾病侵袭性相关的肿瘤生物学的过程中，我们目前正在比较两组切除患者肿瘤的基因表达谱：其中一组在切除后生存期较短（7个月），另一组生存期较长（24-70个月），并进一步验证了以下假设：a)炎性基因驱动切除患者的肿瘤侵袭性；b)炎性相关基因特征定义可切除PDAC的侵袭性亚型。

One of the major challenges in pancreatic cancer research is the availability of clinical samples from patients undergoing surgical resection with complete demographic and clinico-pathological information. In our ongoing efforts, we have been successful in establishing multiple cohorts of resected pancreatic cancer samples from cases in the United States and abroad. This includes a new approved study protocol to collect tumors and/or blood samples from 500 PDAC cases in the greater Baltimore area with myself as principal investigator. This collection will be an invaluable asset for our pancreatic cancer program. The results from our pilot gene-expression profiling study showed that a lower expression of DPEP1 (dipeptidase 1) in tumors was associated with poorer survival in two independent cohorts of PDAC and was independent of stage and resection margin status (Zhang et. al., PLoS One, 2012). DPEP1 expression was significantly lower in tumors as compared to adjacent non-tumor pancreas from the same patient in both the cohorts. Overexpression of DPEP1 in pancreatic cancer cell lines inhibited cell migration and invasion, and increased the sensitivity to gemcitabine, a first-line drug for treating pancreatic cancer. We also showed that DPEP1 is regulated by EGF/MEK/MAPK pathway, and MEK1/2 inhibitor enhanced DPEP1 expression in vitro. In view of these findings, we propose that re-expression of DPEP1 by novel approaches could be useful for the treatment of PDAC in improving patient survival. Currently, we are testing the hypothesis that DPEP1 inhibits tumor progression in vivo. In our continuing effort of examining the tumor biology associated with disease aggressiveness, we are currently comparing the gene expression profile of tumors in two groups of resected patients: one with a short survival (<7 months) and the other with a longer survival (24-70 months) following resection, and further testing the hypotheses that a) Inflammatory genes drive tumor aggressiveness in resected patients and b) Inflammation-associated gene signature defines aggressive subtypes in resectable PDAC.