RESUMEN
Epithelial to mesenchymal transition (EMT) is a complex cellular program that alters epithelial cells and induces their transformation into mesenchymal cells. While essential to normal developmental processes such as embryogenesis and wound healing, EMT has also been linked to the development and progression of various diseases, including fibrogenesis and tumorigenesis. Under homeostatic conditions, initiation of EMT is mediated by key signaling pathways and pro-EMT-transcription factors (EMT-TFs); however, in certain contexts, these pro-EMT regulators and programs also drive cell plasticity and cell stemness to promote oncogenesis as well as metastasis. In this review, we will explain how EMT and EMT-TFs mediate the initiation of pro-cancer states and how they influence late-stage progression and metastasis in pancreatic ductal adenocarcinoma (PDAC), the most severe form of pancreatic cancer.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Transición Epitelial-Mesenquimal , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Factores de Transcripción/metabolismo , Línea Celular Tumoral , Movimiento Celular , Neoplasias PancreáticasRESUMEN
The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-ß) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis.
Asunto(s)
Carcinoma Ductal Pancreático , Proteínas de Unión al ADN , Neoplasias Pancreáticas , Proteína Smad4 , Factores de Transcripción , Animales , Humanos , Ratones , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína Smad4/genética , Proteína Smad4/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Neoplasias PancreáticasRESUMEN
A long-standing question in the pancreatic ductal adenocarcinoma (PDAC) field has been whether alternative genetic alterations could substitute for oncogenic KRAS mutations in initiating malignancy. Here, we report that Neurofibromin1 (NF1) inactivation can bypass the requirement of mutant KRAS for PDAC pathogenesis. An in-depth analysis of PDAC databases reveals various genetic alterations in the NF1 locus, including nonsense mutations, which occur predominantly in tumors with wild-type KRAS. Genetic experiments demonstrate that NF1 ablation culminates in acinar-to-ductal metaplasia, an early step in PDAC. Furthermore, NF1 haploinsufficiency results in a dramatic acceleration of KrasG12D-driven PDAC. Finally, we show an association between NF1 and p53 that is orchestrated by PML, and mosaic analysis with double markers demonstrates that concomitant inactivation of NF1 and Trp53 is sufficient to trigger full-blown PDAC. Together, these findings open up an exploratory framework for apprehending the mechanistic paradigms of PDAC with normal KRAS, for which no effective therapy is available.