κB-Ras and Ral GTPases regulate acinar to ductal metaplasia during pancreatic adenocarcinoma development and pancreatitis.
Acinar Cells
/ metabolism
Aged
Animals
Carcinoma, Pancreatic Ductal
/ genetics
Cell Line, Tumor
Female
GTP Phosphohydrolases
/ genetics
Gene Expression Regulation
Humans
I-kappa B Proteins
/ genetics
Kaplan-Meier Estimate
Male
Metaplasia
/ genetics
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Pancreatic Neoplasms
/ genetics
Pancreatitis
/ genetics
Proteins
/ genetics
SOX9 Transcription Factor
/ genetics
ral GTP-Binding Proteins
/ genetics
ras Proteins
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 07 2020
08 07 2020
Historique:
received:
29
10
2019
accepted:
16
06
2020
entrez:
10
7
2020
pubmed:
10
7
2020
medline:
1
9
2020
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality and therapy resistance. Here, we show that low expression of κB-Ras GTPases is frequently detected in PDAC and correlates with higher histologic grade. In a model of KRas
Identifiants
pubmed: 32641778
doi: 10.1038/s41467-020-17226-0
pii: 10.1038/s41467-020-17226-0
pmc: PMC7343838
doi:
Substances chimiques
I-kappa B Proteins
0
Proteins
0
SOX9 Transcription Factor
0
GTP Phosphohydrolases
EC 3.6.1.-
ral GTP-Binding Proteins
EC 3.6.5.2
ras Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3409Subventions
Organisme : NCI NIH HHS
ID : R01 CA206556
Pays : United States
Références
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. Cancer J. Clin. 68, 7–30 (2018).
Rahib, L. et al. Projecting Cancer Incidence and Deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).
pubmed: 24840647
Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N. & Depinho, R. A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 20, 1218–1249 (2006).
pubmed: 16702400
Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
pubmed: 14706336
Cox, A. D. & Der, C. J. Ras history: the saga continues. Small GTPases 1, 2–27 (2010).
pubmed: 21686117
pmcid: 3109476
Eser, S., Schnieke, A., Schneider, G. & Saur, D. Oncogenic KRAS signalling in pancreatic cancer. Br. J. Cancer 111, 817–822 (2014).
pubmed: 24755884
pmcid: 4150259
Baer, R. et al. Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α. Genes Dev. 28, 2621–2635 (2014).
pubmed: 25452273
pmcid: 4248293
Eser, S. et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23, 406–420 (2013).
pubmed: 23453624
Hill, R. et al. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 70, 7114–7124 (2010).
pubmed: 20807812
pmcid: 2940963
Stanger, B. Z. et al. Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 8, 185–195 (2005).
pubmed: 16169464
Ying, H. et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discov. 1, 158–169 (2011).
pubmed: 21984975
pmcid: 3186945
Collisson, E. A. et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2, 685–693 (2012).
pubmed: 22628411
pmcid: 3425446
Lim, K. H. et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 7, 533–545 (2005).
pubmed: 15950903
Bodemann, B. O. & White, M. A. Ral GTPases and cancer: linchpin support of the tumorigenic platform. Nat. Rev. Cancer 8, 133–140 (2008).
pubmed: 18219307
Chien, Y. & White, M. A. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 4, 800–806 (2003).
pubmed: 12856001
pmcid: 1326339
Ziv, O., Glaser, B. & Dor, Y. The plastic pancreas. Dev. Cell 26, 3–7 (2013).
pubmed: 23867225
Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).
pubmed: 23201164
pmcid: 3568632
Morris, J. P., Cano, D. A., Sekine, S., Wang, S. C. & Hebrok, M. β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Invest. 120, 508–520 (2010).
pubmed: 20071774
pmcid: 2810083
Zhu, L., Shi, G., Schmidt, C. M., Hruban, R. H. & Konieczny, S. F. Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. Am. J. Pathol. 171, 263–273 (2007).
pubmed: 17591971
pmcid: 1941579
Friedlander, S. Y. G. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).
Habbe, N. et al. Spontaneous induction of murine pancreatic intraepithelial neoplasia (mPanIN) by acinar cell targeting of oncogenic Kras in adult mice. Proc. Natl Acad. Sci. USA 105, 18913–18918 (2008).
pubmed: 19028870
Oeckinghaus, A. et al. κB-Ras proteins regulate both NF-κB-dependent inflammation and Ral-dependent proliferation. Cell Rep. 8, 1793–1807 (2014).
pubmed: 25220458
pmcid: 4177457
Fenwick, C. et al. A subclass of Ras proteins that regulate the degradation of IkappaB. Science 287, 869–873 (2000).
pubmed: 10657303
Chen, Y., Wu, J. & Ghosh, G. KappaB-Ras binds to the unique insert within the ankyrin repeat domain of IkappaBbeta and regulates cytoplasmic retention of IkappaBbeta x NF-kappaB complexes. J. Biol. Chem. 278, 23101–23106 (2003).
pubmed: 12672800
Chen, Y. et al. Inhibition of NF-kappaB activity by IkappaBbeta in association with kappaB-Ras. Mol. Cell Biol. 24, 3048–3056 (2004).
pubmed: 15024091
pmcid: 371134
Tago, K., Funakoshi-Tago, M., Sakinawa, M., Mizuno, N. & Itoh, H. KappaB-Ras is a nuclear-cytoplasmic small GTPase that inhibits NF-kappaB activation through the suppression of transcriptional activation of p65/RelA. J. Biol. Chem. 285, 30622–30633 (2010).
pubmed: 20639196
pmcid: 2945557
Shirakawa, R. et al. Tuberous sclerosis tumor suppressor complex-like complexes act as GTPase-activating proteins for Ral GTPases. J. Biol. Chem. 284, 21580–21588 (2009).
pubmed: 19520869
pmcid: 2755882
Gridley, S., Chavez, J. A., Lane, W. S. & Lienhard, G. E. Adipocytes contain a novel complex similar to the tuberous sclerosis complex. Cell Signal. 18, 1626–1632 (2006).
pubmed: 16490346
Feig, L. A. Ral-GTPases: approaching their 15 minutes of fame. Trends Cell Biol. 13, 419–425 (2003).
pubmed: 12888294
Karin, M. Nuclear factor-kappaB in cancer development and progression. Nature 441, 431–436 (2006).
pubmed: 16724054
Karin, M. NF- B as a critical link between inflammation and cancer. Cold Spring Harb. Perspect. Biol. 1, a000141–a000141 (2009).
pubmed: 20066113
pmcid: 2773649
Prabhu, L., Mundade, R., Korc, M., Loehrer, P. J. & Lu, T. Critical role of NF-κB in pancreatic cancer. Oncotarget 5, 10969–10975 (2014).
pubmed: 25473891
pmcid: 4294354
Postler, T. S. & Ghosh, S. Bridging the gap: a regulator of NF-κB linking inflammation and cancer. J. Oral. Biosci. 57, 143–147 (2015).
pubmed: 26273209
pmcid: 4530520
Gannon, M., Herrera, P. L. & Wright, C. V. Mosaic Cre-mediated recombination in pancreas using the pdx-1 enhancer/promoter. Genesis 26, 143–144 (2000).
pubmed: 10686611
Jørgensen, M. C. et al. An illustrated review of early pancreas development in the mouse. Endocr. Rev. 28, 685–705 (2007).
pubmed: 17881611
Klein, W. M., Hruban, R. H., Klein-Szanto, A. J. P. & Wilentz, R. E. Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod. Pathol. 15, 441–447 (2002).
pubmed: 11950919
Zińczuk, J. et al. Expression of chosen cell cycle and proliferation markers in pancreatic intraepithelial neoplasia. Prz. Gastroenterol. 13, 118–126 (2018).
pubmed: 30002770
pmcid: 6040105
Dorrell, C. et al. Isolation of mouse pancreatic alpha, beta, duct and acinar populations with cell surface markers. Mol. Cell. Endocrinol. 339, 144–150 (2011).
pubmed: 21539888
pmcid: 3112273
Chen, X.-W. et al. A Ral GAP complex links PI 3-kinase/Akt signaling to RalA activation in insulin action. Mol. Biol. Cell 22, 141–152 (2011).
pubmed: 21148297
pmcid: 3016972
Bodempudi, V. et al. Ral overactivation in malignant peripheral nerve sheath tumors. Mol. Cell. Biol. 29, 3964–3974 (2009).
pubmed: 19414599
pmcid: 2704746
Urano, T., Emkey, R. & Feig, L. A. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J. 15, 810–816 (1996).
pubmed: 8631302
pmcid: 450279
Vigil, D. et al. Aberrant overexpression of the Rgl2 Ral small GTPase-specific guanine nucleotide exchange factor promotes pancreatic cancer growth through Ral-dependent and Ral-independent mechanisms. J. Biol. Chem. 285, 34729–34740 (2010).
pubmed: 20801877
pmcid: 2966088
Storz, P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 14, 296–304 (2017).
pubmed: 28270694
pmcid: 6036907
Chen, N.-M. et al. NFATc1 links EGFR signaling to induction of Sox9 transcription and acinar–ductal transdifferentiation in the pancreas. Gastroenterology 148, 1024–1034.e9 (2015).
pubmed: 25623042
pmcid: 4409493
Hessmann, E. et al. NFATc4 regulates Sox9 gene expression in acinar cell plasticity and pancreatic cancer initiation. Stem Cells Int. 2016, 5272498 (2016).
pubmed: 26697077
Storz, P. Acinar cell plasticity and development of pancreatic ductal adenocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 14, 296–304 (2017).
pubmed: 28270694
pmcid: 6036907
Al-Adsani, A. et al. Dexamethasone treatment induces the reprogramming of pancreatic acinar cells to hepatocytes and ductal cells. PLoS ONE 5, e13650 (2010).
pubmed: 21048969
pmcid: 2965100
Chuvin, N. et al. Acinar-to-ductal metaplasia induced by transforming growth factor beta facilitates KRAS G12D-driven pancreatic tumorigenesis. Cell. Mol. Gastroenterol. Hepatol. 4, 263–282 (2017).
pubmed: 28752115
pmcid: 5524227
Lynn, F. C. et al. Sox9 coordinates a transcriptional network in pancreatic progenitor cells. Proc. Natl Acad. Sci. USA 104, 10500–10505 (2007).
pubmed: 17563382
Ji, B. et al. Ras activity levels control the development of pancreatic diseases. Gastroenterology 137, 1072–1082.e6 (2009).
pubmed: 19501586
pmcid: 2789008
Ardito, C. M. et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 22, 304–317 (2012).
pubmed: 22975374
pmcid: 3443395
Navas, C. et al. EGF receptor signaling is essential for K-Ras oncogene-driven pancreatic ductal adenocarcinoma. Cancer Cell 22, 318–330 (2012).
pubmed: 22975375
pmcid: 3601542
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
pubmed: 17349585
Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).
pubmed: 21665147
pmcid: 4890723
De Lisle, R. C. & Logsdon, C. D. Pancreatic acinar cells in culture: expression of acinar and ductal antigens in a growth-related manner. Eur. J. Cell Biol. 51, 64–75 (1990).
pubmed: 2184038
Sandgren, E. P., Luetteke, N. C., Palmiter, R. D., Brinster, R. L. & Lee, D. C. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell 61, 1121–1135 (1990).
pubmed: 1693546
Payne, S. N. et al. PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors. Oncogenesis 4, e169–e169 (2015).
pubmed: 26436951
pmcid: 4632089
Elghazi, L. et al. Regulation of pancreas plasticity and malignant transformation by Akt signaling. Gastroenterology 136, 1091–1103.e8 (2009).
pubmed: 19121634
Albury, T. M. et al. Constitutively active Akt1 cooperates with KRasG12D to accelerate in vivo pancreatic tumor onset and progression. Neoplasia 17, 175–182 (2015).
pubmed: 25748236
pmcid: 4351297
Wong, C. H., Li, Y. J. & Chen, Y. C. Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer. World J. Gastroenterol. 22, 7046–7057 (2016).
pubmed: 27610015
pmcid: 4988312
Karlsen, T. A., Jakobsen, R. B., Mikkelsen, T. S. & Brinchmann, J. E. microRNA-140 targets RALA and regulates chondrogenic differentiation of human mesenchymal stem cells by translational enhancement of SOX9 and ACAN. Stem Cells Dev. 23, 290–304 (2014).
pubmed: 24063364
Tsuda, M. et al. The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis. J. Clin. Invest. 128, 3475–3489 (2018).
pubmed: 30010625
pmcid: 6063489
Shih, H. P. et al. A gene regulatory network cooperatively controlled by Pdx1 and Sox9 governs lineage allocation of foregut progenitor cells. Cell Rep. 13, 326–336 (2015).
pubmed: 26440894
pmcid: 4607666
Prévot, P.-P. et al. Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia. Gut 61, 1723–1732 (2012).
pubmed: 22271799
pmcid: 3898034
Lim, K. H. et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr. Biol. 16, 2385–2394 (2006).
pubmed: 17174914
Neel, N. F. et al. The RalB small GTPase mediates formation of invadopodia through a GTPase-activating protein-independent function of the RalBP1/RLIP76 effector. Mol. Cell Biol. 32, 1374–1386 (2012).
pubmed: 22331470
pmcid: 3318593
Saito, R. et al. Downregulation of Ral GTPase-activating protein promotes tumor invasion and metastasis of bladder cancer. Oncogene 32, 894–902 (2013).
pubmed: 22450745
Rao, P. et al. IkappaBbeta acts to inhibit and activate gene expression during the inflammatory response. Nature https://doi.org/10.1038/nature09283 (2010).
Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013).
pubmed: 24157548
pmcid: 3969860
Stock, K. et al. Neovascular prostate-specific membrane antigen expression is associated with improved overall survival under palliative chemotherapy in patients with pancreatic ductal adenocarcinoma. Biomed. Res. Int. 2017, 1–8 (2017).