scholarly journals Uncovering potential interventions for pancreatic cancer patients via mathematical modeling

2022 ◽  
Author(s):  
Daniel R Plaugher ◽  
Boris Aguilar ◽  
David Murrugarra
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Stellate Cell ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Stellate Cell ◽  
Control Sets ◽  
Stochastic Simulator ◽  
The Impact

Pancreatic Ductal Adenocarcinoma (PDAC) is widely known for its poor prognosis because it is often diagnosed when the cancer is in a later stage. We built a model to analyze the microenvironment of pancreatic cancer in order to better understand the interplay between pancreatic cancer, stellate cells, and their signaling cytokines. Specifically, we have used our model to study the impact of inducing four common mutations: KRAS, TP53, SMAD4, and CDKN2A. After implementing the various mutation combinations, we used our stochastic simulator to derive aggressiveness scores based on simulated attractor probabilities and long-term trajectory approximations. These aggression scores were then corroborated with clinical data. Moreover, we found sets of control targets that are effective among common mutations. These control sets contain nodes within both the pancreatic cancer cell and the pancreatic stellate cell, including PIP3, RAF, PIK3 and BAX in pancreatic cancer cell as well as ERK and PIK3 pancreatic stellate cell. Many of these nodes were found to be differentially expressed among pancreatic cancer patients in the TCGA database. Furthermore, literature suggests that many of these nodes can be targeted by drugs currently in circulation. The results herein help provide a proof of concept in the path towards personalized medicine through a means of mathematical systems biology. All data and code used for running simulations, statistical analysis, and plotting is available on a GitHub repository at https://github.com/drplaugher/PCC_Mutations .

DNAJA1 dysregulates metabolism promoting an anti-apoptotic phenotype in pancreatic ductal adenocarcinoma

2020 ◽  
Author(s):  
Heidi Roth ◽  
Fatema Bhinderwala ◽  
Rodrigo Franco ◽  
You Zhou ◽  
Robert Powers
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
The Impact

Abstract BackgroundAt less than 7%, pancreatic ductal adenocarcinoma (PDAC) has one of the poorest 5-year cancer survival rates and is set to be the leading cause of cancer related deaths by 2030. The co-chaperone protein DNAJA1 (HSP40) is downregulated four-fold in pancreatic cancer cells, but its impact on pancreatic ductal adenocarcinoma (PDAC) progression remains unclear.MethodsDNAJA1 was overexpressed in pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2, through retroviral transfection. The impact of overexpressing DNAJA1 was investigated using a combination of untargeted metabolomics, stable isotope resolved metabolomics (SIRM), confocal microscopy, flow-cytometry, and cell-based assays.ResultsPancreatic cancer cells overexpressing DNAJA1 exhibited a global metabolomic change. Specifically, differential output from Warburg glycolysis, an increase in redox currency, and an alteration in amino acid levels were observed in both overexpression cell lines. DNAJA1 overexpression also led to mitochondrial fusion, an increase in the expression of Bcl-2, a modest protection from redox induced cell death, a loss of structural integrity due to the loss of actin fibers, and an increase in cell invasiveness in BxPC-3. These differences were more pronounced in BxPC-3, which contains a loss-of-function mutation in the tumor suppressing gene SMAD4.ConclusionsThe overexpression of DNAJA1 promoted cellular proliferation, redox tolerance, invasiveness, and anti-apoptosis, which suggests DNAJA1 has numerous regulatory roles. Overall, our findings suggest a proto-oncogenic role of DNAJA1 in PDAC progression and suggests DNAJA1 may function synergistically with other proteins with altered activity in pancreatic cancer cell lines.

1133 PANCREATIC STELLATE CELL AND CANCER CELL DERIVED EXOSOMES IMPAIR BETA CELL FUNCTION: IMPLICATIONS FOR PANCREATIC CANCER RELATED DIABETES.

2020 ◽  
Vol 158 (6) ◽  
pp. S-221
Author(s):  
Chamini Perera ◽  
Zhihong Xu ◽  
Alpha Raj Mekapogu ◽  
S.M. Zahid Hosen ◽  
Srinivasa Pothula ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Beta Cell ◽  
Cancer Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Stellate Cell ◽  
Pancreatic Stellate Cell

Prediction of gemcitabine resistance in patients with pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4125-4125
Author(s):  
S. Nakahira ◽  
S. Nakamori ◽  
M. Tsujie ◽  
J. Okami ◽  
I. Takemasa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Patients ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Human Pancreatic Cancer ◽  
Clinical Effects ◽  
Resistant Variant ◽  
Altered Expression ◽  
Gemcitabine Resistance ◽  
Recurrent Pancreatic Cancer

4125 Background: Pancreatic cancer is the most lethal of all solid tumors partially because of its chemoresistance. Although a deoxycytidine analogue, gemcitabine, is widely used as a first selected and a single agent for the treatment of this disease despite low response rate, molecular mechanisms of gemcitabine resistance in pancreatic cancer still remain obscure. The purpose of this study is to identify the molecular marker for gemcitabine resistance in human pancreatic cancer. Methods: Gemcitabine resistant variants were established from human pancreatic cancer cell lines, MiaPaCa2. Gene expression changes between parental cells and resistant cells were assessed by an oligonucleotide microarray covering 30,000 human oligonucleotides, and candidate genes were validated by RT-PCR and Western blotting. The association to resistance was validated by RNAi assay. Clinical effects on 18 recurrent pancreatic cancer patients treated by gemcitabine were evaluated using mRNA of specimens resected at the primary operation. Results: The 81-fold gemcitabine resistant variant MiaPaCa2-RG was selected from pancreatic cancer cell line MiaPaCa2. By microarray analysis between parental and resistant MiaPaCa2 cells, 99.6% genes were altered expression of less than 2-fold. Among 43 genes with altered expression of more than 2-fold, the most up-regulated gene in MiaPaCa2-RG cells is ribonucleotide reductase M1 subunit (RRM1) with 4.5-fold up-regulation compared with MiaPaCa2 cells. Transfection with RRM1-specific RNAi suppressed more than 90% of RRM1 mRNA and protein expression both in MiaPaCa2 and MiaPaCa2-RG cells. After RRM1-specific RNAi transfection, gemcitabine chemoresistance of MiaPaCa2-RG was significantly reduced to the same level of MiaPaCa2. The 18 recurrent pancreatic cancer patients were divided into two groups by RRM1 mRNA expression levels. There was a significant association between gemcitabine response and RRM1 expression (p = 0.018). Furthermore, patients with high RRM1 levels had a poor survival times after gemcitabine treatment than those with low RRM1 levels (p = 0.016). Conclusions: RRM1 should be a key molecule in gemcitabine resistance in pancreatic cancer through both in vitro and clinical models. RRM1 should be considered as the predictor of gemcitabine resistance. No significant financial relationships to disclose.

scholarly journals Transcriptional regulation of SLIT2 expression in pancreatic cancer cell lines

2020 ◽  
Author(s):  
Brenna A. Rheinheimer ◽  
Lukas Vrba ◽  
Bernard W Futscher ◽  
Ronald L Heimark
Keyword(s):  
Pancreatic Cancer ◽  
Transcriptional Regulation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Trichostatin A ◽  
Cancer Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Liver Cancers

AbstractBackgroundSLIT2 has been shown to serve as a tumor suppressor in breast, lung, colon, and liver cancers. Additionally, expression of SLIT2 has been shown to be epigenetically regulated in prostate cancer. Therefore, we sought to determine transcriptional regulation of SLIT2 in pancreatic ductal adenocarcinoma.MethodsRNA expression of SLIT2, SLIT3, and ROBO1 was examined in a panel of pancreatic ductal adenocarcinoma cell lines while protein expression of ROBO1 and SLIT2 was examined in tumor tissue. Methylation of the SLIT2 promoter was determined using Sequenom while histone modifications were queried by chromatin immunoprecipitation. Reexpression of SLIT2 was tested by treatment with 5-aza-2’deoxycytidine and Trichostatin A.ResultsPancreatic cancer cell lines fall into three distinct groups based on SLIT2 and ROBO1 expression. The SLIT2 promoter is methylated in pancreatic ductal adenocarcinoma and SLIT2 expression is dependent on the level of methylation at specific CpG sites. Treatment with 5-aza-2’deoxycytidine (but not Trichostatin A) led to SLIT2 reexpression. The SLIT2 promoter is bivalent in pancreatic ductal adenocarcinoma and histone marks around the transcriptional start site are responsible for transcription.ConclusionsLoss of SLIT2 expression modulated by epigenetic silencing may play a role in pancreatic ductal adenocarcinoma progression.

scholarly journals Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer

2016 ◽  
Vol 310 (11) ◽  
pp. G1124-G1137 ◽  
Author(s):  
Christina Vorvis ◽  
Maria Hatziapostolou ◽  
Swapna Mahurkar-Joshi ◽  
Marina Koutsioumpa ◽  
Jennifer Williams ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Network Analyses ◽  
Invasion Mechanisms

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates and limited therapeutic options. Thus elucidation of signaling pathways involved in PDAC pathogenesis is essential for identifying novel potential therapeutic gene targets. Here, we used a systems approach to elucidate those pathways by integrating gene and microRNA profiling analyses together with CRISPR/Cas9 technology to identify novel transcription factors involved in PDAC pathogenesis. FOXA2 transcription factor was found to be significantly downregulated in PDAC relative to control pancreatic tissues. Functional experiments revealed that FOXA2 has a tumor suppressor function through inhibition of pancreatic cancer cell growth, migration, invasion, and colony formation. In situ hybridization analysis revealed miR-199a to be significantly upregulated in pancreatic cancer. Bioinformatics and luciferase analyses showed that miR-199a negatively but directly regulates FOXA2 expression through binding in its 3′-untranslated region (UTR). Evaluation of the functional importance of miR-199a on pancreatic cancer revealed that miR-199a acts as an inhibitor of FOXA2 expression, inducing an increase in pancreatic cancer cell proliferation, migration, and invasion. Additionally, gene ontology and network analyses in PANC-1 cells treated with a small interfering RNA (siRNA) against FOXA2 revealed an enrichment for cell invasion mechanisms through PLAUR and ERK activation. FOXA2 deletion (FOXA2Δ) by using two CRISPR/Cas9 vectors in PANC-1 cells induced tumor growth in vivo resulting in upregulation of PLAUR and ERK pathways in FOXA2Δ xenograft tumors. We have identified FOXA2 as a novel tumor suppressor in pancreatic cancer and it is regulated directly by miR-199a, thereby enhancing our understanding of how microRNAs interplay with the transcription factors to affect pancreatic oncogenesis.

scholarly journals GATA4 Regulates Inflammation-Driven Pancreatic Ductal Adenocarcinoma Progression

2021 ◽  
Vol 9 ◽  
Author(s):  
Weiliang Jiang ◽  
Congying Chen ◽  
Li Huang ◽  
Jie Shen ◽  
Lijuan Yang
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Pancreatic Cancer Cell ◽  
Differential Expression Analysis ◽  
Ductal Adenocarcinoma ◽  
Cancer Cell Invasion ◽  
Dibutyltin Dichloride ◽  
Inflammatory Stimuli

Cancer-associated inflammation is a key molecular feature in the progression of pancreatic ductal adenocarcinoma (PDAC). GATA4 is a transcription factor that participates in the regulation and normal development of several endoderm- and mesoderm-derived tissues such as the pancreas. However, it remains unclear whether GATA4 is involved in the inflammation-driven development of pancreatic cancer. Here, we employed quantitative reverse transcription PCR, immunohistochemistry, and differential expression analysis to investigate the association between GATA4 and inflammation-driven PDAC. We found that overexpression of GATA4 in pancreatic tumor tissue was accompanied by increased levels of inflammatory macrophages. We used macrophage-conditioned medium to validate inflammation models following treatment with varying concentrations of lipopolysaccharide and determined whether GATA4-dependent inflammatory stimuli affected pancreatic cancer cell invasion and growth in vitro. Nude mouse models of dibutyltin dichloride-induced chronic pancreatitis with orthotopic tumor xenografts were used to evaluate the effect of the inflammatory microenvironment on GATA4 expression in vivo. Our findings indicate that overexpression of GATA4 dramatically aggravated inflammatory stimuli-induced pancreatic cancer cell invasion and growth via NF-κB and STAT3 signaling, whereas silencing of GATA4 attenuated invasion and growth. Overall, our findings suggest that inflammation-driven cancer progression is dependent on GATA4 expression and is mediated through the STAT3 and NF-κB signaling pathways.

scholarly journals Inhibition of Sphingosine-1-Phosphate signaling in pancreatic ductal adenocarcinoma leads to downregulation of growth and invasion

2020 ◽  
Author(s):  
Brenna A. Rheinheimer ◽  
Alex Cardenas ◽  
Luis Camacho ◽  
Evan S. Ong ◽  
Tun Jie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Growth ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Leading Edge ◽  
Cancer Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Sphingosine 1 Phosphate

AbstractBackgroundDeregulated phosphorylation of sphingosine by the sphingosine kinases and signaling through the EDG family of receptors enhances growth and survival in many cell types. Therefore, we sought to elucidate the effect of alterations in the ceramide/sphingosine/S1P rheostat on driving human pancreatic ductal adenocarcinoma towards a malignant phenotype.MethodsPancreatic cancer cell lines were treated with exogenous S1P, FTY720, and siRNA to Sphk1. Migration was evaluated by wound healing assays, cell growth by MTT assays, and invasion by tumorsphere assays. Expression of S1PR1, S1PR3, Sphk1, and Sphk2 were measured by quantitative PCR, western blot, and immunohistochemistry.ResultsS1PR1, S1PR3, and Sphk2 were overexpressed in all pancreatic cancer cell lines. Sphk1 translocated from the cytoplasm to the nucleus in cells located at the leading edge of cell clusters. Exogenous S1P increased cell migration while treatment with FTY720 and Sphk1 siRNA decreased cell growth and invasion.ConclusionsOur results suggest that increased S1PR1 expression may be an early event in pancreatic cancer pathogenesis. Additionally, altered Sphk1 localization may provide a mechanism through which pancreatic ductal adenocarcinoma cells at the leading edge invade into the surrounding matrix. Finally, inhibition of sphingosine-1-phosphate signaling may provide a novel therapeutic target for patients with metastatic disease.

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