Despite tremendous scientific efforts aimed at understanding the molecular biology of pancreatic cancer, conventional treatment approaches have had little impact on the course of the disease. Thus, studies identifying key determinants in pancreatic cancer and pancreatic cancer stem cell (CSCs) can provide both biomarkers of PDAC aggressiveness and potentially optimal targets to overcome chemoresistance. We have found that NFATc1 and NFATc2 (NFATc1/c2) are ectopically expressed in PDAC samples, respectively and that pharmacologic inhibition or RNAi toward NFATc1/c2 reduces PDAC cell growth in vitro and in vivo. Interestingly, we show that expression of a constitutive nuclear NFATc1 in the developing mouse pancreas using p48-cre along with KRasG12D develop invasive PDAC by 16-20 weeks of age, thus demonstrating that NFATc1 is a potent oncogene in this disease. We performed NFATc1 ChIP-seq in order to gain insight into the transcriptional network driven by this oncogenic/inflammatory transcription factor. We identified nearly 1800 NFATc1-target genes, two-thirds of which are dependent on an interaction with STAT3. Significantly, most of the NFAT/STAT3-regulated gene networks are involved in inflammation, proliferation and metastasis. Moreover, we demonstrate for the first time that NFATc1 is enriched in pancreatic CSCs generated from PDAC cell lines and CSC self-renewal is inhibited by pharmacologically targeting NFAT nuclear activity through the use of cyclosporine A (CsA). However, the mechanisms by which NFATs regulate CSC self-renewal and or chemoresistance are unclear. Furthermore, we show that PDAC cell lines, which express NFATc1/c2 are sensitive to CsA and synergize with gemcitabine to kill tumor cells in vitro and limit tumor growth in vivo. Despite these preliminary observations, information regarding NFATc1/c2 target genes in human PDAC is lacking and mechanisms by which NFATc1/c2 regulate pancreatic cancer cell growth remain to be determined. Furthermore it is unknown whether ectopic expression of NFATc1/c2 correlates with specific clinical features of the disease, participates in pancreatic CSC biology, or represents a therapeutic target in the clinic. These outstanding questions will be addressed in this application.

Public Health Relevance

We have found that NFAT transcription factors are ectopically expressed in PDAC. It is our hypothesis that further delineation of the transcriptome regulated by NFATc1 and NFATc2 in human PDAC will identify potential biomarkers that correlate with clinical parameters. Moreover, the use of cyclosporine A, which targets NFAT activity and is widely used to prevent organ transplant rejection, could be used to treat PDAC patients expressing NFAT transcription factors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA102701-11A1
Application #
8738911
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
2014-09-18
Project End
2019-08-31
Budget Start
2014-09-18
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$284,103
Indirect Cost
$105,422
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
McWilliams, Robert R; Wieben, Eric D; Chaffee, Kari G et al. (2018) CDKN2A Germline Rare Coding Variants and Risk of Pancreatic Cancer in Minority Populations. Cancer Epidemiol Biomarkers Prev 27:1364-1370
Supekar, Nitin T; Lakshminarayanan, Vani; Capicciotti, Chantelle J et al. (2018) Synthesis and Immunological Evaluation of a Multicomponent Cancer Vaccine Candidate Containing a Long MUC1 Glycopeptide. Chembiochem 19:121-125
Cohen, Joshua D; Li, Lu; Wang, Yuxuan et al. (2018) Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359:926-930
Zhang, Mingfeng; Lykke-Andersen, Soren; Zhu, Bin et al. (2018) Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues. Gut 67:521-533
Kanamori, Karina S; de Oliveira, Guilherme C; Auxiliadora-Martins, Maria et al. (2018) Two Different Methods of Quantification of Oxidized Nicotinamide Adenine Dinucleotide (NAD+) and Reduced Nicotinamide Adenine Dinucleotide (NADH) Intracellular Levels: Enzymatic Coupled Cycling Assay and Ultra-performance Liquid Chromatography (UPLC)-Mass Bio Protoc 8:
Hu, Chunling; Hart, Steven N; Polley, Eric C et al. (2018) Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. JAMA 319:2401-2409
Orozco, Carlos A; Martinez-Bosch, Neus; Guerrero, Pedro E et al. (2018) Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor-stroma crosstalk. Proc Natl Acad Sci U S A 115:E3769-E3778
Radecki Breitkopf, Carmen; Wolf, Susan M; Chaffee, Kari G et al. (2018) Attitudes Toward Return of Genetic Research Results to Relatives, Including After Death: Comparison of Cancer Probands, Blood Relatives, and Spouse/Partners. J Empir Res Hum Res Ethics 13:295-304
Antwi, Samuel O; Fagan, Sarah E; Chaffee, Kari G et al. (2018) Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status. J Natl Cancer Inst :
Cobo, Isidoro; Martinelli, Paola; Flández, Marta et al. (2018) Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554:533-537

Showing the most recent 10 out of 336 publications