Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas (original) (raw)
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YAP1 Oncogene is a Context-specific Driver for Pancreatic Ductal Adenocarcinoma
2018
ObjectiveYap1 oncogene is essential for KRAS-induced pancreatic ductal adenocarcinoma (PDAC) initiation. We recently demonstrated that YAP1 is capable of bypassing KRAS-dependency. However, genetic alterations of YAP1 pathway are rare in human PDAC and its role in tumor maintenance remains unclear. This study investigates YAP1 function in transcriptionally distinct subsets of PDAC and explores the molecular mechanisms for YAP1 activation.DesignConditional Yap1 allele was crossed into LSL-KrasG12D/+; Trp53R172H/+; Mist1-CreERT2+ mice to study the requirement of Yap1 for PDAC development in adult mice. YAP1 function in advanced PDAC was analyzed in human tissues, PDAC cell lines, patient-derived xenograft samples and mouse PDAC cells, using in vitro and in vivo assays and gene expression analyses. WNT5A expression and its effect on YAP1 activation as well as tumorigenic activity was studied in aforementioned human and mouse systems using genetic and pharmacological approaches. The byp...
PAF1 cooperates with YAP1 in metaplastic ducts to promote pancreatic cancer
Cell Death & Disease
Acinar-to-ductal metaplasia (ADM) is a precursor lesion of pancreatic ductal adenocarcinoma (PDAC); however, the regulators of the ADM-mediated PDAC development and its targeting are poorly understood. RNA polymerase II-associated factor 1 (PAF1) maintains cancer stem cells leading to the aggressiveness of PDAC. In this study, we investigated whether PAF1 is required for the YAP1-mediated PDAC development and whether CA3 and verteporfin, small molecule inhibitors of YAP1/TEAD transcriptional activity, diminish pancreatic cancer (PC) cell growth by targeting the PAF1/YAP1 axis. Here, we demonstrated that PAF1 co-expresses and interacts with YAP1 specifically in metaplastic ducts of mouse cerulein- or KrasG12D-induced ADM and human PDAC but not in the normal pancreas. PAF1 knockdown (KD) reduced SOX9 in PC cells, and the PC cells showed elevated PAF1/YAP1 complex recruitment to the promoter of SOX9. The PAF1 KD reduced the 8xTEAD and SOX9 promoter-luciferase reporter activities in the...
Cancers
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies, characterized by aggressive biological behavior and a lack of response to currently available chemotherapy. Emerging evidence has identified epithelial to mesenchymal transition (EMT) as a key driver of PDAC progression and a central regulator in the development of drug resistance. EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors. Activation of EMT transcriptional reprogramming converts cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. EMT occurrence in pre-invasive pancreatic lesions has been implicated in early PDAC dissemination. Moreover, cancer cell phenotypic plasticity driven by EMT contributes to intratumoral heterogeneity and drug tolerance and is mechanistically associated with the emergence of cells e...
Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer
eLife, 2019
Pancreatic ductal adenocarcinoma (PDA) is a heterogeneous disease comprised of a basal-like subtype with mesenchymal gene signatures, undifferentiated histopathology and worse prognosis compared to the classical subtype. Despite their prognostic and therapeutic value, the key drivers that establish and control subtype identity remain unknown. Here, we demonstrate that PDA subtypes are not permanently encoded, and identify the GLI2 transcription factor as a master regulator of subtype inter-conversion. GLI2 is elevated in basal-like PDA lines and patient specimens, and forced GLI2 activation is sufficient to convert classical PDA cells to basal-like. Mechanistically, GLI2 upregulates expression of the pro-tumorigenic secreted protein, Osteopontin (OPN), which is especially critical for metastatic growth in vivo and adaptation to oncogenic KRAS ablation. Accordingly, elevated GLI2 and OPN levels predict shortened overall survival of PDA patients. Thus, the GLI2-OPN circuit is a driver...
A shifting adversary: control of pancreatic cancer transcriptomic subtypes
Journal of Cancer Metastasis and Treatment, 2022
Cellular plasticity, the dynamic ability of cells to adopt distinct transcriptional states, plays a well-known role in the pancreas during the initiation of pancreatic ductal adenocarcinoma (PDA), the most common form of pancreatic cancer. It is now becoming clear that plasticity also plays an important role after the emergence of PDA. PDA is composed of two major transcriptional subtypes, classical and basal-like, with important biological differences. Recent work has indicated that individual tumors can be comprised of cells of each subtype, and that tumor subtype can change during the evolution of a tumor. This suggests that PDA cells can transit between transcriptional states, with important implications for disease progression. This review discusses what is currently known about inter-subtype plasticity and how this process is controlled.
PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance
Genes & development, 2016
Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA), making developmental regulators therapeutically attractive. Here we demonstrate diverse functions for pancreatic and duodenal homeobox 1 (PDX1), a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of pancreatic intraepithelial neoplasia (PanIN)-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor-suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing epithelial-to-mesenchymal transition (EMT), and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA,...
Transcriptional dissection of pancreatic tumors engrafted in mice
Genome medicine, 2014
Background: Engraftment of primary pancreas ductal adenocarcinomas (PDAC) in mice to generate patient-derived xenograft (PDX) models is a promising platform for biological and therapeutic studies in this disease. However, these models are still incompletely characterized. Here, we measured the impact of the murine tumor environment on the gene expression of the engrafted human tumoral cells. Methods: We have analyzed gene expression profiles from 35 new PDX models and compared them with previously published microarray data of 18 PDX models, 53 primary tumors and 41 cell lines from PDAC. The results obtained in the PDAC system were further compared with public available microarray data from 42 PDX models, 108 primary tumors and 32 cell lines from hepatocellular carcinoma (HCC). We developed a robust analysis protocol to explore the gene expression space. In addition, we completed the analysis with a functional characterization of PDX models, including if changes were caused by murine environment or by serial passing. Results: Our results showed that PDX models derived from PDAC, or HCC, were clearly different to the cell lines derived from the same cancer tissues. Indeed, PDAC-and HCC-derived cell lines are indistinguishable from each other based on their gene expression profiles. In contrast, the transcriptomes of PDAC and HCC PDX models can be separated into two different groups that share some partial similarity with their corresponding original primary tumors. Our results point to the lack of human stromal involvement in PDXs as a major factor contributing to their differences from the original primary tumors. The main functional differences between pancreatic PDX models and human PDAC are the lower expression of genes involved in pathways related to extracellular matrix and hemostasis and the up-regulation of cell cycle genes. Importantly, most of these differences are detected in the first passages after the tumor engraftment. Conclusions: Our results suggest that PDX models of PDAC and HCC retain, to some extent, a gene expression memory of the original primary tumors, while this pattern is not detected in conventional cancer cell lines. Expression changes in PDXs are mainly related to pathways reflecting the lack of human infiltrating cells and the adaptation to a new environment. We also provide evidence of the stability of gene expression patterns over subsequent passages, indicating early phases of the adaptation process.
Molecular biology of pancreatic cancer
Clinical and Translational Oncology, 2008
Pancreatic ductal adenocarcinoma is a dismal disease with a median survival of less than 6 months and an overall 5-year survival rate less than 1% . This bad prognosis is due to early lymphatic and hematogenic dissemination. Effective therapies for locally advanced or metastatic tumors are very limited and curatively resected patients experience relapse in over 80% of cases. Together, these findings reflect the aggressive biology of the disease. Here, we describe molecular mechanisms leading to unrestrained proliferation, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, tissue invasion, metastasis and sustained angiogenesis. Potential therapeutic targets are highlighted.
Biomedicines
Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system’s role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment.