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Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling
Open accessAbstract
Missense mutations in the p53 tumor suppressor inactivate its antiproliferative properties but can also promote metastasis through a gain-of-function activity. We show that sustained expression of mutant p53 is required to maintain the prometastatic phenotype of a murine model of pancreatic cancer, a highly metastatic disease that frequently displays p53 mutations. Transcriptional profiling and functional screening identified the platelet-derived growth factor receptor b (PDGFRb) as both necessary and sufficient to mediate these effects. Mutant p53 induced PDGFRb through a cell-autonomous mechanism involving inhibition of a p73/NF-Y complex that represses PDGFRb expression in p53-deficient, noninvasive cells. Blocking PDGFRb signaling by RNA interference or by small molecule inhibitors prevented pancreatic cancer cell invasion in vitro and metastasis formation in vivo. Finally, high PDGFRb expression correlates with poor disease-free survival in pancreatic, colon, and ovarian cancer patients, implicating PDGFRb as a prognostic marker and possible target for attenuating metastasis in p53 mutant tumors.
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“altered p53 function has a multitude of tumor-promoting effects on neoplastic cells, including increased genomic instability30, reprogrammed cellular metabolism57,58, and enhanced metastatic propensity59.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [59]
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The indolent nature of pulmonary metastases from ductal adenocarcinoma of the pancreas
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Self-citationCancer Stemness: p53 at the Wheel
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“In pancreatic cancers, mutant p53 activates the NF-Y transcription complex by releasing p73, resulting in transactivation of PDFGR-b (Figure 3A), promoting cell migration, while in glioblastoma PTEN promotes the association of mutant p53 with NF-Y to induce expression of Myc and Bcl-XL (110, 122).”
BackgroundMutant p53 as a Regulator and Target of Autophagy
Shi, Y., Norberg, E., & Vakifahmetoglu-Norberg, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.607149 · Cited by 77
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“Interestingly, p53 was shown to promote gluconeogenesis [76], while oncogenic Gain-of-Function mutations of p53, reported to impact on expression of NF-Y genes [77, 78], mediate metabolic reprogramming and increased glycolysis [79]: it will be interesting to evaluate the effects of mutp53 on the metabolic genes target…”
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“…DEVELOPMENT 31:1339–1353 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/17; www.genesdev.org 1339 and helped uncover potential targetable vulnerabilities in p53 mutant breast cancer (Freed-Pastor et al. 2012) and pancreatic ductal adenocarcinoma (PDAC) (Weissmueller et al. 2014).”
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Ferraiuolo, M. A., Agostino, S. D., Blandino, G., & Strano, S. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00077 · Cited by 72
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“The significant modules of WGCNA were involved in ECM regulation, metabolism correction pathways, PI3K-Akt signaling pathway and platelet derived growth factor signaling pathway, which have been widely studied in PC (Vaquero et al., 2003; Stoll et al., 2005; Weissmueller et al., 2014).”
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“In addition, mutp53 showsa “ gain of function(GOF) ” effect thatcanfurther leadto cisplatin resistance 14 – 16 .”
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“Concerning PDGF receptors, high PDGFRb expression was found to be correlated with poor disease-free survival in pancreatic cancer and additionally colon and ovarian cancer patients [35].”
BackgroundMutant p53 Drives Cancer Metastasis via RCP-Mediated Hsp90α Secretion
Zhang, S., Wang, C., Ma, B., Xu, M., Xu, S., Liu, J., Tian, Y., Fu, Y., & Luo, Y. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107879 · Cited by 61
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Mutant p53 Protein and the Hippo Transducers YAP and TAZ: A Critical Oncogenic Node in Human Cancers
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“Due to its high binding affinity to p73, mutant p53 disables the inhibitory complex p73/NF-Y promoting the oncogenic expression of PDGFRb in pancreatic cancer metastasis [198].”
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“Moreover, silencing mp53 with RNAi induces massive apoptosis and diminishes the metastatic potential of cancer cells [38-43].”
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“As well as the high rate of KRAS activating mutations, sequence analysis has shown that PDACs demonstrate a mixture of tumor suppressor gene mutations, with TP53 being mutated or inactivated in 75% of PDAC and mutant TP53 being shown to drive pancreatic cancer (48).”
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“For example, the missense mutation of p53 (mp53), existing in approximately 50% of human cancers, confers oncogenic properties to mp53 that contribute to cancer progression and metastasis [39-41].”
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“The mutant p53 (mutp53) may not only lose its tumor-suppressor functions, it may also acquire oncogenic gain of function (GOF) [7-9].”
Backgroundp53 Gain-of-Function Mutation Induces Metastasis via BRD4-Dependent CSF-1 Expression
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Self-citationPbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning
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“systems; however the biological function of PDGFR regulation by these TFs in vivo remains elusive (Ballagi et al., 1995; Uramoto et al., 2004; Jin et al., 2008; Weissmueller et al., 2014).”
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Exploiting the p53 Pathway for TherapyPreprint
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“A recent example is the inhibition of PDGFRb by the FDA-approved agent imatinib that, as a single agent, led to the striking reduction of tumor metastases in a mouse model of pancreatic ductal adenocarcinoma, which expresses p53R172H (Weissmueller et al. 2014).”
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“Transcriptional profiling and functional screening have identified PDGFRβ as both necessary and sufficient to mediate the proliferative and pro-metastatic effects of mutant p53 (25).”
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“…down-regulation of Dicer through p63-dependent and -independent means (Muller et al. 2014), inhibition of PDGFRb by blocking the p73/NF-Y complex (Weissmueller et al. 2014), and interactions with NRG1 and Pin1 (Girardini et al. 2011; Coffill et al. 2012). mut-p53 AFFECTS TUMOR STROMA AND…”
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“GOF-TP53 mutations result in a fibrotic tumor microenvironment [63].”
BackgroundHDAC2 Facilitates Pancreatic Cancer Metastasis
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“…network to TGF b , EMT, and PI3K pathways, combined with published data, demonstrating that PDGFR b is a driver of PDAC metastasis (55, 56) and that PI3K – AKT signaling is relevant to escape the proapoptotic functionofTGF b (59),contributestoexplainthereducedmetastasisof Hdac2 -de fi…”
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Redox Regulation of Cancer Metastasis: Molecular Signaling and Therapeutic Opportunities
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“Mutant p53 drives pancreatic cancer metastasis via cellautonomous platelet derived growth factor (PDGF) receptor β signaling [Weissmueller et al., 2014].”
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p53, a potential predictor of Helicobacter pylori infection-associated gastric carcinogenesis?
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“Mutant p53 proteins acquire tumour-promoting functions that enhance cell growth, proliferation, survival, and motility [35, 36] p53 mutations are generally divided into two categories: DNA-interacting mutants that directly alter amino acids and structural mutants that lead to the unfolding of p53 protein, which is cri…”
BackgroundWullweber, A., Strick, R., Lange, F., Sikic, D., Taubert, H. W., Wach, S., Wullich, B., Bertz, S., Weyerer, V., Stoehr, R., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2336 · Cited by 47
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Pancreatic Cancer Progression Relies upon Mutant p53-Induced Oncogenic Signaling Mediated by NOP14
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“Interestingly, several of the above-mentioned genes have been reported to be direct or indirect effectors of p53 in diverse cancers.(2-3, 12-14) To determine whether these genes are regulated by mutp53 in PDAC cells, qRT-PCR and immunoblotting analyses were performed and we found that mutp53 inhibition led to increase…”
BackgroundInfluentialTargeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study
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“27 28–30 MDM2 is an oncoprotein containing an ubiquitin E3 ligase, and gene amplification and overexpression of MDM2 are observed in more than 17% of human tumors.”
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ELL targets c-Myc for proteasomal degradation and suppresses tumour growth
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“[60] have shown that promotion of metastasis in mutant p53 cells is induced through platelet-derived growth factor receptor b (PDGFRb), and this in turn could be a prognostic marker and possible target for clinical trials.”
BackgroundA Therapeutic Strategy for Resectable Pancreatic Cancer Based on Risk Factors of Early Recurrence
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“19-22 Differential gene expression involved in pancreatic cancer metastasis included upregulation of Pdgfrb 23 and Cldn9 (and downregulation of Cldn1 24 ).”
Pathology, genetics and precursors of human and experimental pancreatic neoplasms: An update
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“Indeed, there is a report that mutant p53 induces PDGFRb (platelet derived growth factor receptor beta) through a cellautonomous mechanism involving the inhibition of a p73/ NF-Y complex that represses PDGFRb expression in p53deficient, noninvasive cells [69].”
BackgroundEpigenetic synthetic lethality approaches in cancer therapy
Yang, H., Cui, W., & Wang, L. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0734-x · Cited by 37
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Molecular and Metabolic Subtypes Correspondence for Pancreatic Ductal Adenocarcinoma Classification
Espiau-Romera, P., Courtois, S., Parejo-Alonso, B., & Sancho, P. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9124128 · Cited by 43
“Importantly, mutant P53 may contribute to metastatic progression of K-RAS-driving PDAC-bearing mice, highlighting a novel role of this transcription factor in late stages of PDAC beyond the malignant transformation of PanINs into PDAC [26,27].”
BackgroundAnti-tumoral effect of desmethylclomipramine in lung cancer stem cells
Bongiorno‐Borbone, L., Giacobbe, A., Compagnone, M., Eramo, A., Maria, R. D., Peschiaroli, A., & Melino, G. (2015) · Oncotarget · doi:10.18632/oncotarget.4700 · Cited by 38
“The most significant evidence involving p53 in cancer is its high mutation rate in cancers as well as its ability, when mutated, to drive cancer metastasis [83-89].”
BackgroundYallowitz, A. R., Li, D., Lobko, A., Mott, D., Nemajerová, A., & Marchenko, N. D. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0360 · Cited by 36
“It was previously shown that depletion of mutp53 decreases invasion in vitro (18, 38, 39, 46) and metastases in mice (39, 46).”
BackgroundMutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma
Schofield, H. K., Zeller, J., Espinoza, C. E., Halbrook, C. J., Vecchio, A. D., Magnuson, B., Fabo, T., Daylan, A. E. C., Kovalenko, I., Lee, H., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.97422 · Cited by 38
“Given the changes in in vitro migration, and the increased muscle invasion observed in subcutaneous models, we implanted KCip53-1 cells orthotopically into the pancreata of immunocompromised mice to determine whether mutant p53R270H expression conferred increased metastatic potential, as previously described for p53R1…”
BackgroundMethodInfluentialGain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis
Roszkowska, K. A., Giziński, S., Sady, M., Gajewski, Z., & Olszewski, M. B. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21041334 · Cited by 37
“These include sequestration and inactivation of p63 and p73 that has been observed in mouse models [52] and demonstrated to promote metastasis [53,54].”
BackgroundHuang, H., Chang, C., Wang, C., & Lin, K. (2021) · Cells · doi:10.3390/cells10010067 · Cited by 37
“Pancreatic cancer TGFβ1 Chemoresistance [97] PDGFB p53, PDGFRb Metastasis [99]”
BackgroundFunctional Diversity of p53 in Human and Wild Animals
Li, Y., Zhang, M., Xu, X., Zhao, Y., Chatoo, M., Zhu, T., Deng, H., Nevo, E., Du, J.-Z., & Chen, X. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00152 · Cited by 36
Yu, Z., Wang, H., Fang, Y., Lu, L., Li, M., Yan, B., Nie, Y., & Teng, C. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.29455 · Cited by 35
PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer
Xia, W., Bai, H., Deng, Y., & Yang, Y. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15832 · Cited by 36
Li, B., An, W., Wang, H., Baslan, T., Mowla, S., Krishnan, A., Xiao, W., Koche, R. P., Liu, Y., Cai, S. F., et al. (2022) · Blood · doi:10.1182/blood.2021014465 · Cited by 38
Self-citationPan, M., Jiang, C., Zhang, Z., Achacoso, N. S., Alexeeff, S., Solorzano, A. V., Tse, P., Chung, E. H., Sundaresan, T. K., Suga, J. M., et al. (2023) · JCO Precision Oncology · doi:10.1200/po.22.00570 · Cited by 38
Carbone, M., Amelio, I., Affar, E. B., Brugarolas, J., Cannon‐Albright, L., Cantley, L. C., Cavenee, W. K., Chen, Z. J., Croce, C. M., D’Andrea, A. D., et al. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0213-5 · Cited by 37
Self-citationβ-catenin-activated autocrine PDGF/Src signaling is a therapeutic target in pancreatic cancer
Kuo, T., Cheng, K., Shan, Y., Chen, L., & Hung, W.-C. (2018) · Theranostics · doi:10.7150/thno.28201 · Cited by 35
“Both KPA and KPC cancer cells expressed PDGFR-α and PDGFR-β mRNA (Figure S6A); however, their protein levels were low, in accordance with findings from a previous study [20].”
ResultAKT1/FOXP3 axis-mediated expression of CerS6 promotes p53 mutant pancreatic tumorigenesis
Qi, D., Song, X., Xue, C., Yao, W., Shen, P., Yu, H. T., & Zhang, Z. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.06.024 · Cited by 35
Wu, M., An, J., Zheng, Q., Xin, X., Lin, Z., Li, X., Li, H., & Lu, D. (2016) · Oncotarget · doi:10.18632/oncotarget.9089 · Cited by 34
Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer
Wong, C. H., Li, Y., & Chen, Y. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i31.7046 · Cited by 34
Ets2 anchors the prometastatic function of mutant p53 in osteosarcomaPreprint
Liu, D. D., & Kang, Y. (2017) · Genes & Development · doi:10.1101/gad.307439.117 · Cited by 34
“For example, mutant p53 can bind to and disrupt the function of other p53 family proteins, including TAp63 and p73, thereby promoting proliferation and metastasis by affecting the expression of downstream genes (Lang et al. 2004; Weissmueller et al. 2014).”
BackgroundPitter, K. L., Grbovic-Huezo, O., Joost, S., Singhal, A., Blum, M., Wu, K., Holm, M., Ferrena, A., Bhutkar, A. J., Hudson, A., et al. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-1742 · Cited by 35
Deciphering the significance of p53 mutant proteins
Butera, A., & Amelio, I. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2024.06.003 · Cited by 36
Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression
Pan, Z., Li, L., Fang, Q., Zhang, Y., Hu, X., Qian, Y., & Huang, P. (2018) · Cancer Cell International · doi:10.1186/s12935-018-0718-5 · Cited by 33
“in the p53 tumor suppressor inactivated its antiproliferative properties but could also promote metastasis through a gain-of-function activity [24].”
BackgroundAbrams, S. L., Lertpiriyapong, K., Yang, L. V., Martelli, A. M., Cocco, L., Ratti, S., Falasca, M., Murata, R. M., Rosalen, P. L., Lombardi, P., et al. (2018) · Advances in Biological Regulation · doi:10.1016/j.jbior.2018.06.002 · Cited by 36
The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis
Xiong, S., Pant, V., Zhang, Y., Aryal, N. K., You, M. J., Kusewitt, D. F., & Lozano, G. (2016) · The Journal of Pathology · doi:10.1002/path.4854 · Cited by 32
“Mutant p53 shows gain-of-function activities through multiple downstream regulators and pathways, including activation of the mevalonate pathway [35], chromatin methyltransferases and acetyltransferases [36], transforming growth factor-β/p63 [37], platelet-derived growth factor receptor-β [38], and Pla2g16 [30].”
BackgroundKumar, S., Inigo, J. R., Kumar, R., Chaudhary, A. K., O’Malley, J., Balachandar, S., Wang, J., Attwood, K. M., Yadav, N., Hochwald, S. N., et al. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.10.029 · Cited by 32
NF-Y Overexpression in Liver Hepatocellular Carcinoma (HCC)
Bezzecchi, E., Ronzio, M., Mantovani, R., & Dolfini, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239157 · Cited by 32
Sunami, Y., Häußler, J., Zourelidis, A. A., & Kleeff, J. H. (2022) · Cancers · doi:10.3390/cancers14030744 · Cited by 36
“With cancer cells isolated from KPC mice, it has been demonstrated that Trp53 mutations drive pancreatic cancer metastasis through PDGF receptor β (PDGFR-β) signaling [29].”
BackgroundSabe, H. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01130-3 · Cited by 29
Masuda, T., Fukuda, A., Yamakawa, G., Omatsu, M., Namikawa, M., Sono, M., Fukunaga, Y., Nagao, M., Araki, O., Yoshikawa, T., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci161847 · Cited by 32
“This study was also supported by the Takeda Foundation (2019056665), Princess Takamatsu Cancer Research Fund (17-24924), Mitsubishi Foundation (201910037, 281119), Uehara Foundation (201720143), Naito Foundation (20829-1), Kobayashi Foundation, Shimizu Foundation, Japan Foundation for Applied Enzymology, Astellas Foun…”
BackgroundResultAllele-specific silencing of mutant p53 attenuates dominant-negative and gain-of-function activities
Iyer, S. V., Parrales, A., Begani, P., Narkar, A., Adhikari, A. S., Martinez, L. A., & Iwakuma, T. (2015) · Oncotarget · doi:10.18632/oncotarget.6634 · Cited by 31
“These p53 mutants frequently show oncogenic gain-of-function (GOF) activities, such as enhanced metastatic potential and drug resistance [5-8].”
BackgroundOtaka, Y., Rokudai, S., Kaira, K., Fujieda, M., Horikoshi, I., Kawabata‐Iwakawa, R., Yoshiyama, S., Yokobori, T., Ohtaki, Y., Shimizu, K., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-1815 · Cited by 31
“Indeed, the oncogenic properties of mutated or amplified PDGFRa have been studied in several tumor types, and PDGFRb has been linked to not only tumor angiogenesis via paracrine effects but also cancer metastasis (30, 31).”
BackgroundSelf-citationSuppression of HSF1 activity by wildtype p53 creates a driving force for p53 loss-of-heterozygosity
Isermann, T., Sener, Ö. C., Stender, A., Klemke, L., Winkler, N., Neeße, A., Li, J., Wegwitz, F., Moll, U. M., & Schulz‐Heddergott, R. (2021) · Nature Communications · doi:10.1038/s41467-021-24064-1 · Cited by 31
The animal nuclear factor Y: an enigmatic and important heterotrimeric transcription factor.
Li, G., Zhao, H., Wang, L., Wang, Y., Guo, X., & Xu, B. (2018) · Europe PMC (PubMed Central) · Cited by 36
Systematically identify key genes in inflammatory and non-inflammatory breast cancer
Chai, F., Liang, Y., Zhang, F., Wang, M., Zhong, L., & Jiang, J. (2015) · Gene · doi:10.1016/j.gene.2015.09.025 · Cited by 31
Metadata
- Authors
- Weissmueller, S., Manchado, E., Saborowski, M., Morris, J. P., Wagenblast, E., Davis, C. A., Moon, S.-H., Pfister, N. T., Tschaharganeh, D. F., Kitzing, T., Aust, D., Markert, E. K., Wu, J., Grimmond, S. M., Pilarsky, C., Prives, C., Biankin, A. V., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- Columbia University (US)
- Technische Universität Dresden (DE)
- Institute for Advanced Study (US)
- Garvan Institute of Medical Research (AU)
- The University of Queensland (AU)
- Corresponding author
- Lowe, Scott W.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 157
- Issue
- 2
- Pages
- 382-394
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4001090
- OpenAlex
- W2088441464
- Cited by
- 466
- References
- 61
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 16 · 2023: 42 · 2022: 42 · 2021: 54 · 2020: 43 · 2019: 32 · 2018: 48 · 2017: 59 · 2016: 50 · 2015: 33 · 2014: 18
- FWCI
- 25.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- Cancer Research UK (17263)
- National Cancer Institute (P01CA087497, P01CA129243, CA 013106, P01CA013106, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- mutant p53, pancreatic cancer, metastasis, PDGF receptor beta, gain-of-function p53, cell invasion, prognostic factors, small molecule inhibitors, RNA interference, tumor suppressor inactivation
- MeSH terms
- Animals, Disease Models, Animal, Humans, Neoplasm Metastasis, Pancreatic Neoplasms, Tumor Suppressor Protein p53, Receptor, Platelet-Derived Growth Factor beta, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, Mice
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