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.
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.
|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|
|Razidlo, Gina L; Burton, Kevin M; McNiven, Mark A (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293:11143-11153|
|Chaker, Mahmoud; Minden, Audrey; Chen, Suzie et al. (2018) Rho GTPase effectors and NAD metabolism in cancer immune suppression. Expert Opin Ther Targets 22:9-17|
|Sugimoto, Motokazu; Farnell, Michael B; Nagorney, David M et al. (2018) Decreased Skeletal Muscle Volume Is a Predictive Factor for Poorer Survival in Patients Undergoing Surgical Resection for Pancreatic Ductal Adenocarcinoma. J Gastrointest Surg 22:831-839|
|Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604|
|Paradise, Brooke D; Barham, Whitney; Fernandez-Zapico, Martín E (2018) Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes? Cancers (Basel) 10:|
|Hogan, Kelly A; Cho, Dong Seong; Arneson, Paige C et al. (2018) Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment. Cytokine 107:9-17|
|Tarragó, Mariana G; Chini, Claudia C S; Kanamori, Karina S et al. (2018) A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell Metab 27:1081-1095.e10|
|Chini, Eduardo N; Chini, Claudia C S; Espindola Netto, Jair Machado et al. (2018) The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. Trends Pharmacol Sci 39:424-436|
Showing the most recent 10 out of 336 publications