Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression

Palagani, Vindhya; Bożko, Przemysław; Khatib, Mona El; Belahmer, Hanane; Giese, Nathalia A.; Sipos, Bence; Malek, Nisar P.; Plentz, Ruben R.

doi:10.1093/carcin/bgt394

Cited by 59 publications

(36 citation statements)

References 38 publications

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“…22 This pathway has a prominent role in initiation and progression of PDAC 23 and is widely known for its role in cell proliferation, migration, invasion and apoptosis. 24 STAT3 is one of the isoforms of STAT protein family that is constitutively activated in most cancers in response to growth factors and cytokines.…”

Section: Resultsmentioning

confidence: 99%

Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

et al. 2014

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Pancreatic cancer is the only major cancer with very low survival rates (1%). It is the fourth leading cause of cancer-related death. Hyperactivated growth hormone receptor (GHR) levels have been shown to increase the risk of cancer in general and this pathway is a master regulator of key cellular functions like proliferation, apoptosis, differentiation, metastasis, etc. However, to date there is no available data on how GHR promotes pancreatic cancer pathogenesis. Here, we used an RNA interference approach targeted to GHR to determine whether targeting GHR is an effective method for controlling pancreatic cancer growth and metastasis. For this, we used an in vitro model system consisting of HPAC and PANC-1 pancreatic cancer cells lines. GHR is upregulated in both of these cell lines and silencing GHR significantly reduced cell proliferation and viability. Inhibition of GHR also reduced the metastatic potential of pancreatic cancer cells, which was aided through decreased colony-forming ability and reduced invasiveness. Flow cytometric and western blot analyses revealed the induction of apoptosis in GHR silenced cells. GHR silencing affected phosphatidylinositol 3 kinase/AKT, mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase, Janus kinase/signal transducers and activators of transcription and mammalian target of rapamycin signaling, as well as, epithelial to mesenchymal transition. Interestingly, silencing GHR also suppressed the expression of insulin receptor-β and cyclo-oxygenease-2. Altogether, GHR silencing controls the growth and metastasis of pancreatic cancer and reveals its importance in pancreatic cancer pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

et al. 2014

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“…Tissue microarray construction and immunohistochemistry have been performed as described before [57]. …”

Section: Methodsmentioning

confidence: 99%

Role of BCL9L in transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) has a low overall survival rate, which is approximately 20% during the first year and decreases to less than 6% within five years of the disease. This is due to premature dissemination accompanied by a lack of disease-specific symptoms during the initial stages. Additionally, to date there are no biomarkers for an early prognosis available.A growing number of studies indicate that epithelial to mesenchymal transition (EMT), triggered by WNT-, TGF-β- and other signaling pathways is crucial for the initiation of the metastatic process in PDAC. Here we show, that BCL9L is up-regulated in PDAC cell lines and patient tissue compared to non-cancer controls. RNAi-induced BCL9L knockdown negatively affected proliferation, migration and invasion of pancreatic cancer cells. On a molecular basis, BCL9L depletion provoked an increment of E-cadherin protein levels, with concomitant increase of β-catenin retention at the plasma membrane. This is linked to the induction of a strong epithelial phenotype in pancreatic cancer cells upon BCL9L knockdown even in the presence of the EMT-inducer TGF-β. Finally, xenograft mouse models of pancreatic cancer revealed a highly significant reduction in the number of liver metastases upon BCL9L knockdown. Taken together, our findings underline the key importance of BCL9L for EMT and thus progression and metastasis of pancreatic cancer cells. Direct targeting of this protein might be a valuable approach to effectively antagonize invasion and metastasis of PDAC.

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“…Thus, PRKD1 brings together two important pathways that drive the formation of precancerous lesions. Notch can also act synergistically with other transcription factors such as STAT3 and the combined inhibition of Notch and JAK2–STAT3 signalling in Kras LSL-G12D/+ ; Trp53 −/+ ; Pdx1- Cre (KPC) mice has been shown to impair ADM and its progression 93 .…”

Section: Oncogene-driven Irreversible Admmentioning

confidence: 99%

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

Störz

2017

Nat Rev Gastroenterol Hepatol

266

273

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Acinar cells in the adult pancreas show high plasticity and can undergo transdifferentiation to a progenitor-like cell type with ductal characteristics. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. Data from animal models show that cells that undergo ADM in response to oncogenic signalling are precursors for pancreatic intraepithelial neoplasia lesions, which can further progress to pancreatic ductal adenocarcinoma (PDAC). As human pancreatic adenocarcinoma is often diagnosed at a stage of metastatic disease, understanding the processes that lead to its initiation is important for the discovery of markers for early detection, as well as options that enable an early intervention. Here, the critical determinants of acinar cell plasticity are discussed, in addition to the intracellular and extracellular signalling events that drive acinar cell metaplasia and their contribution to development of PDAC.

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Combined inhibition of Notch and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression

Cited by 59 publications

References 38 publications

Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

Growth hormone receptor inhibition decreases the growth and metastasis of pancreatic ductal adenocarcinoma

Role of BCL9L in transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal-transition (EMT) and metastasis of pancreatic cancer

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

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