Cell-Autonomous and Non-Autonomous Roles for TGF-beta Signaling in Pancreatic Cancer Metastasis

Pancreatic Cancer;Metastasis;Transforming Growth Factor Beta Signaling;not listed

Macgregor-Das, Anne MarieJaffee, Elizabeth ;

Johns Hopkins University

关键词: Pancreatic Cancer;    Metastasis;    Transforming Growth Factor Beta Signaling;    not listed;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60537/MACGREGOR-DAS-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Pancreatic cancer is an almost universally lethal disease, with five-year survival rates approaching 6%.Its dismal prognosis is a consequence of several factors, including a lack of early detection methods, the inherent aggressive nature of this disease, and largely ineffective therapeutic regimens. Moreover, an overwhelming majority of patients are diagnosed at an advanced stage after their tumor has already metastasized.Decades of research have shed light onto the genes and signaling pathways that drive pancreatic carcinogenesis and progression. The transforming growth factor-beta (TGFβ) signaling pathway is often perturbed in pancreatic cancer, with alterations to the key transcription factor SMAD4 being observed in over half of all tumors. Paradoxically, TGFβ exerts both tumor suppressive and tumor-promoting influences. TGFβ suppresses tumor formation by regulating cell cycle progression and promoting apoptosis. However, it can also promote tumor progression by both cell autonomous and non-autonomous signaling mechanisms, namely, by promoting epithelial-mesenchymal transition, stromal deposition, and immune evasion.In pancreatic cancer, SMAD4 loss portends a worse prognosis and is correlated with widely metastatic disease. The goal of this thesis was to further understand the relationship between TGFβ signaling and metastatic efficiency in pancreatic cancer, with a particular interest on how TGFβ signaling in the tumor epithelium influences the tumor microenvironment.Using a novel conditional mouse model of pancreatic cancer, we show that reduced TGFβ signaling in invasive PDA results in the oligometastatic phenotype whereas oncogenic TGFβ signaling promotes widely metastatic disease. Additionally, inactivation of either TGFβR2 or SMAD4 in pancreatic cancer cells alters the immune response in invasive disease by mediating the accumulation of regulatory immune cell subsets. It will be important to further investigate how TGFβ signaling facilitates the recruitment and polarization of these cells into tumors and the extent to which it influences their function in order to fully appreciate their contributions to progression and metastasis in pancreatic cancer.