Novel aspects of Epithelial-Mesenchymal Transition(EMT)in pancreatic cancer

描述（由申请人提供）：胰腺导管腺癌（PDAC）是一种致命的恶性肿瘤，总5年生存率为6%。促进PDAC生物侵袭性的分子机制正在逐渐被阐明，PDAC中高频和低频驱动突变的关键作用为了解这种癌症的复杂性提供了新的见解。然而，在存在致癌性Kras和视网膜母细胞瘤蛋白功能丧失的背景下，PDAC中异常转化生长因子- β (tgf - β)作用的广泛后果尚不清楚。在本提案中，我们将使用我们生成的一种新的PDAC基因工程小鼠模型（GEM），其中致癌Kras与RB缺失相结合。由此产生的KRC小鼠在出生后几周内迅速发展为胰腺上皮内（PanIN）病变，并发展为PDAC，这些癌症中的胰腺癌细胞具有高度增殖性。基于我们已发表的数据和初步结果，KRC小鼠将允许我们验证PDAC中异常tgf - β信号与RB失活协同作用的假设，从而导致tgf - β的有害作用，异常有丝分裂信号，增强胰腺癌细胞增殖和癌细胞间质相互作用。我们将评估RB功能丧失对tgf - β信号传导的影响，评估tgf - β信号传导在PDAC转移中的作用，并描述炎症细胞因子和Wnt通路对胰腺癌细胞增殖和基质形成的贡献。为此，我们将使用从KRC胰腺建立的细胞系，使用我们实验室产生的其他具有高转移发生率的PDAC新型gem，对这些gem进行治疗干预，并评估这些途径在人类PDAC中的作用。这些建议的研究将以高影响的方式推进我们对PDAC病理生物学的理解，并将为抑制癌症生长和转移指明新的治疗方法。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with an overall 5-year survival rate of 6%. The molecular mechanisms that contribute to the biological aggressiveness of PDAC are being gradually elucidated, and the crucial role of high and low frequency driver mutations in PDAC is providing new insights into the complexity of this cancer. However, the widespread consequences of aberrant transforming growth factor-beta (TGF-beta) actions in PDAC in the context of the presence of oncogenic Kras and loss of function of the retinoblastoma protein are not well understood. In this proposal we will use a novel genetically engineered mouse model (GEM) of PDAC that we generated in which oncogenic Kras is combined with RB deletion. The resultant KRC mice rapidly develop pancreatic intraepithelial (PanIN) lesions that progress to PDAC within weeks after birth, and the pancreatic cancer cells in these cancers are highly proliferative. Based on our published data and preliminary results, the KRC mouse will allow us to test the hypothesis that aberrant TGF-beta signaling in PDAC synergizes with RB inactivation, leading to deleterious actions by TGF-beta, aberrant mitogenic signaling, and enhanced pancreatic cancer cell proliferation and cancer cell-stroma interactions. We will evaluate the effects of RB loss of function on TGF-beta signaling, assess the role of TGF-beta signaling in PDAC metastasis, and delineate the contributions of inflammatory cytokines and Wnt pathways to pancreatic cancer cell proliferation and stroma formation. To this end we will use cell lines established from KRC pancreata, use other novel GEMs of PDAC generated in our laboratory that exhibit a high incidence of metastases, conduct therapeutic interventions in these GEMs, and assess the role of these pathways in human PDAC. The proposed studies will advance our understanding of PDAC pathobiology in a high impact manner, and will point the way to novel therapies for suppressing cancer growth and metastasis.