PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential

Wartenberg, Martin; Centeno, Irene; Haemmig, Stefan; Vassella, Erik; Zlobec, Inti; Galván, José A.; Neuenschwander, Maja; Schlup, Cornelia; Gloor, Beat; Lugli, Alessandro; Perren, Aurel; Karamitopoulou, Evanthia

doi:10.1016/j.ejca.2016.06.013

Cited by 18 publications

(17 citation statements)

References 34 publications

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“…We could recently show that increased levels of miR-21 in stromal cells were associated with the loss of it's target protein PTEN, especially at the microenvironment of the invasive front of pancreatic ductal adenocarcinoma, which correlated with increased metastatic potential. 52 MiR-205 was not dysregulated in the stromal cells in agreement with recently published work depicting miR-205 as a purely epithelial microRNA in pancreatic cancer. 53 This study has several major findings: analysis is based on a well-characterized cohort of pancreatic cancer cases and is designed in a hypothesis-driven approach employing advanced techniques for accurate examination of microRNA levels, while microRNA analysis is performed on human pancreatic cancer tissue reflecting the genuine state of the tumor microenvironment.…”

Section: Discussionsupporting

confidence: 91%

MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer

et al. 2017

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Cellular interactions in the tumor microenvironment influence neoplastic progression in pancreatic ductal adenocarcinoma. One underlying mechanism is the induction of the prognostically unfavorable epithelial-mesenchymal-transition-like tumor budding. Our aim is to explore the expression of microRNAs implicated in the regulation of tumor budding focusing on the microenvironment of the invasive front. To this end, RNA from laser-capture-microdissected material of the main tumor, tumor buds, juxta-tumoral stroma, tumor-remote stroma, and non-neoplastic pancreatic parenchyma from pancreatic cancer cases with (n=7) and without (n=6) tumor budding was analyzed by qRT-PCR for the expression of a panel of miRNAs that are known to be implicated in the regulation of epithelial-mesenchymal transition, including miR-21, miR-183, miR-200b, miR-200c, miR-203, miR-205, miR-210, and miR-217. Here we show that at the invasive front of pancreatic ductal adenocarcinoma, specific microRNAs, are differentially expressed between tumor buds and main tumor cells and between cases with and without tumor budding, indicating their involvement in the regulation of the budding phenotype. Notably, miR-200b and miR-200c were significantly downregulated in the tumor buds. Consistent with this finding, they negatively correlated with the expression of epithelial-mesenchymal-transition-associated E-cadherin repressors ZEB1 and ZEB2 in the budding cells (P<0.001). Interestingly, many microRNAs were also dysregulated in juxta-tumoral compared to tumor-remote stroma suggesting that juxta-tumoral stroma contributes to microRNA dysregulation. Notably, miR-200b and miR-200c were strongly downregulated while miR-210 and miR-21 were upregulated in the juxta-tumoral vs tumor-remote stroma in carcinomas with tumor budding. In conclusion, microRNA targeting in both tumor and stromal cells could represent a treatment option for aggressive pancreatic cancer.

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Section: Discussionsupporting

confidence: 91%

MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer

et al. 2017

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“…Here, we present evidence of a novel regulatory mechanism for MTSS1 stabilization via the canonical tumor suppressor protein PTEN. PTEN expression has been found to be crucial in minimizing the lethality of PDAC through regulation of the PI3K/AKT pathway [22] ; however, its role in PDAC metastasis has only been briefly studied [23] , [24] , [25] . In this manuscript, we demonstrate that loss of PTEN in PDAC cells not only leads to a more invasive and migratory phenotype, but also results in decreased in MTSS1 expression.…”

Section: Introductionmentioning

confidence: 99%

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

et al. 2018

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Pancreatic ductal adenocarcinoma (PDAC) presents at metastatic stage in over 50% of patients. With a survival rate of just 2.7% for patients presenting with distant disease, it is imperative to uncover novel mechanisms capable of suppressing metastasis in PDAC. Previously, we reported that the loss of metastasis suppressor protein 1 (MTSS1) in PDAC cells results in significant increase in cellular migration and invasion. Conversely, we also found that overexpressing MTSS1 in metastatic PDAC cell lines corresponds with not only decreased metastatic phenotype, but also greater overall survival. While it is known that MTSS1 is downregulated in late-stage PDAC, the mechanism behind that loss has not yet been elucidated. Here, we build off our previous findings to present a novel regulatory mechanism for the stabilization of MTSS1 via the tumor suppressor protein phosphatase and tensin homolog (PTEN). We show that PTEN loss in PDAC cells results in a decrease in MTSS1 expression and increased metastatic potential. Additionally, we demonstrate that PTEN forms a complex with MTSS1 in order to stabilize and protect it from proteasomal degradation. Finally, we show that the inflammatory tumor microenvironment, which makes up over 90% of PDAC tumor bulk, is capable of downregulating PTEN expression through secretion of miRNA-23b, potentially uncovering a novel extrinsic mechanism of MTSS1 regulation. Collectively, these data offer new insight into the role and regulation of MTSS1in suppressing tumor cell invasion and migration and help shed light as to what molecular mechanisms could be leading to early cell dissemination in PDAC.

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“…Another similar study has confirmed the tumor suppressive role of PTEN in mice with the KRAS mutation [96]. A study conducted by Wartenberg and co-workers observed that the deletion of PTEN correlates with metastases and reduction in the overall survival of PC patients [97]. This study further suggested that tumor-associated stromal cells are deficient in PTEN protein due to chromosomal abnormality or deletion of PTEN , and such a defective stroma fuels pancreatic tumor cells and enhances the aggressiveness of disease.…”

Section: Molecular Alterations Driving Pancreatic Cancer Progressionmentioning

confidence: 84%

Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward

Khan

Azim

Zubair

et al. 2017

IJMS

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Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.

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PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential

Cited by 18 publications

References 34 publications

MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer

MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward

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