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 multiple tumor-promoting effects on neoplastic cells, including increased genomic instability, reprogrammed cellular metabolism, and enhanced metastatic propensity.
“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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InfluentialTranscriptome analysis by strand-specific sequencing of complementary DNA
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PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis
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InfluentialSelf-citationTAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs
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BackgroundSelf-citationMutant p53 drives invasion in breast tumors through up-regulation of miR-155
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“In addition, mutant p53 has also been reported to drive invasion by regulating several miRNAs, such as miR155 and miR130b (Neilsen et al., 2013; Dong et al., 2013).”
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“previously described (Goulimari et al., 2005; Kitzing et al., 2007).”
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TopBP1 Mediates Mutant p53 Gain of Function through NF-Y and p63/p73
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Gα12/13 Is Essential for Directed Cell Migration and Localized Rho-Dia1 Function
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“previously described (Goulimari et al., 2005; Kitzing et al., 2007).”
Self-citationPDGFRB Promotes Liver Metastasis Formation of Mesenchymal-Like Colorectal Tumor Cells
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“We used the compound crenolanib, a small molecule inhibitor of type III tyrosine kinases, potent against PDGFRa, PDGFRb, and FLT3, but not against other known receptor tyrosine kinases (VEGFR, FGFR), serine/threonine (RAF), or tyrosine kinases (ABL1) (Lewis et al., 2009).”
Targeting Mutant p53 in Human Tumors
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“However, mutant p53 is neither a targetable cell-surface protein nor a druggable enzyme (Levine and Oren, 2009), and novel therapeutic modalities, such as RNAi or restoring wild-type p53 conformations, have yet to show efficacy in clinical studies (Lehmann and Pietenpol, 2012).”
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Self-citationIsolation and Characterization of the Mouse PDGF β-Receptor Promoter
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“…Inc. conserved CCAAT binding motif for NF-Y, a well-characterized heterotrimeric transcriptional activator (NF-YA, NF-YB, and NF-YC) of PDGFRB, where the NF-YB subunit interacts with p73 but is devoid of transcriptional activity (Ballagi et al., 1995; Ishisaki et al., 1997; Serra et al., 1998).”
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Conservation and divergence of NF-Y transcriptional activation function
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“…Inc. conserved CCAAT binding motif for NF-Y, a well-characterized heterotrimeric transcriptional activator (NF-YA, NF-YB, and NF-YC) of PDGFRB, where the NF-YB subunit interacts with p73 but is devoid of transcriptional activity (Ballagi et al., 1995; Ishisaki et al., 1997; Serra et al., 1998).”
Hackzell, A., Uramoto, H., Izumi, H., Kohno, K., & Funa, K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204483200 · Cited by 33 · cited 2× · see citing works
“Because a previous report indicated that p73 can repress the transcription of PDGFRB (Hackzell et al., 2002), and because our KPC cells expressed p73, but not p63, as determined by RNA-seq (data not shown), we aimed to understand whether the physical interaction of mutant p53 with p73 might impair the ability of p73 t…”
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“…Inc. conserved CCAAT binding motif for NF-Y, a well-characterized heterotrimeric transcriptional activator (NF-YA, NF-YB, and NF-YC) of PDGFRB, where the NF-YB subunit interacts with p73 but is devoid of transcriptional activity (Ballagi et al., 1995; Ishisaki et al., 1997; Serra et al., 1998).”
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“Although further studies will be required to explore this notion, pharmacological inhibition of PDGFRb with the tyrosine kinase inhibitor imatinib, in combination with standard chemotherapy, has shown promise in treating metastatic colorectal cancer patients (Hoehler et al., 2013).”
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Genomic analyses identify molecular subtypes of pancreatic cancer
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Self-citationPancreatic cancer: Advances and challenges
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Perturbation-response genes reveal signaling footprints in cancer gene expression
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“…mutations and loss are in line with the recent discovery that TP53 mutations can act in an oncogenic manner in addition to disrupting its tumor suppressor activity, which has been shown for individual cancer types (Olive et al. 2004; Zhang et al. 2013; Weissmueller et al. 2014; Zhu et al. 2015).”
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Self-citationMolecular subtypes of pancreatic cancer
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Self-citationFibroblast heterogeneity in the cancer wound
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Evolving therapeutic landscape of advanced hepatocellular carcinoma
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Cancer-associated fibroblasts in gastrointestinal cancer
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Tumor microenvironment participates in metastasis of pancreatic cancer
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“the expression of PDGF receptor β correlates with poor disease-free survival in pancreatic cancer patients [152, 153].”
BackgroundTargeting mutant p53 for cancer therapy: direct and indirect strategies
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Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others
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Understanding the complexity of p53 in a new era of tumor suppression
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Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth
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Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis
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“…changes to those observed in a prior microarray evaluation of human PDA samples (Moffitt et al., 2015), including upregulation of known regulators of PDA metastasis, Lin28b, Pdgfrb, and Runx3 (Figures S2A and S2B) (Kugel et al., 2016; Weissmueller et al., 2014; Whittle et al., 2015).”
Mutant p53 as a target for cancer treatment
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Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment
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Mutant p53 Suppresses Innate Immune Signaling to Promote Tumorigenesis
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Gain-of-function mutant p53 in cancer progression and therapy
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“Mutp53 sequesters p73 from forming the complex with NF-Y, activating PDGF receptor b (PDGFRb) signaling to promote pancreatic cancer metastasis (Weissmueller et al., 2014).”
BackgroundCell death in pancreatic cancer: from pathogenesis to therapy
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“As a proof of concept we have confirmed expression of 7 proteins; two proteins confirm the origin of the hMSCs EVs (CD90 and CD81) [37] and five known proteins associated with tumor proliferation and anti-metastasis [38-42].”
BackgroundMacrophage PI3Kγ Drives Pancreatic Ductal Adenocarcinoma Progression
Kaneda, M. M., Cappello, P., Nguyen, A. V., Ralainirina, N., Hardamon, C. R., Foubert, P., Schmid, M. C., Sun, P., Mose, E. S., Bouvet, M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1346 · Cited by 330 · see citing works
The enhancement of glycolysis regulates pancreatic cancer metastasis
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“In pancreatic cancer KPC cells, mutant p53R175H and R273H may bind to p73 and prevent its binding to NF-Y on the PDGFRβ promoter, allowing PDGFRβ expression.(18) The TF NF-Y binds the p53 missense mutants R175H and 273C, transactivating pro-cell cycle genes.”
Backgroundα-Ketoglutarate links p53 to cell fate during tumour suppression
Morris, J. P., Yashinskie, J. J., Koche, R., Chandwani, R., Tian, S., Chen, C.-C., Baslan, T., Marinkovic, Z. S., Sánchez-Rivera, F. J., Leach, S. D., et al. (2019) · Nature · doi:10.1038/s41586-019-1577-5 · Cited by 296 · see citing works
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“From this, a single signature was identified (called PC-1) that following crossvalidation could predict survival in the discovery cohort (Fig 1A).”
Self-citationSignaling pathways in cancer‐associated fibroblasts: recent advances and future perspectives
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Self-citationThe kinome 'at large' in cancer
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Molecular Pathogenesis of Pancreatic Cancer
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Therapeutic targeting of tumor suppressor genes
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“able to significantly reduce the invasive potential of models of pancreatic adenocarcinoma.(40)”
BackgroundMutant p53: it’s not all one and the same
Kennedy, M. C., & Lowe, S. W. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-00989-y · Cited by 200 · see citing works
“For example, the best characterized GOF activity of mutant p53 is its role in promoting metastasis [43, 48].”
BackgroundSelf-citationRole and regulation of autophagy in cancer
Rakesh, R., Dharshini, L. C. P., Sakthivel, K. M., & Rasmi, R. R. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166400 · Cited by 196 · see citing works
p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells
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Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer
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“Inducible shRNAs against TP53 and Trp53 (human andmurine p53) or renilla (R) were cloned into the TRMPV-Neo vector (pSIN-TREdsRed-miR30-PGK-Venus-IRES-NeoR) as previously described (Weissmueller et al., 2014; Zuber et al., 2011).”
BackgroundMethodSelf-citationGain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis
Stein, Y., Rotter, V., & Aloni-Grinstein, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246197 · Cited by 161 · see citing works
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“Other work has indicated that mutant p53 mediates PDAC metastasis through upregulation of the receptor tyrosine kinase (RTK), platelet derived growth factor receptor-β (PDGFR-β) (11).”
BackgroundMutant p53 on the Path to Metastasis
Tang, Q., Su, Z., Gu, W., & Rustgi, A. K. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.11.004 · Cited by 153 · see citing works
Osteosarcoma: Molecular Pathogenesis and iPSC Modeling
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“Mutant p53 also upregulates PDGFRb by inhibiting the p73/NF-Y complex, leading to further invasion and metastasis in a pancreatic cancer mouse model [37].”
BackgroundThe p53 family and the hypoxia-inducible factors (HIFs): determinants of cancer progression
Amelio, I., & Melino, G. (2015) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2015.04.007 · Cited by 151 · see citing works
Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression
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Current and Emerging Therapies in Metastatic Pancreatic Cancer
Manji, G. A., Olive, K. P., Saenger, Y. M., & Oberstein, P. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2319 · Cited by 145 · see citing works
TP53 mutations in epithelial ovarian cancer
Zhang, Y., Cao, L., Nguyen, D., & Lu, H. (2016) · Translational Cancer Research · doi:10.21037/tcr.2016.08.40 · Cited by 149 · see citing works
“Similarly, in a pancreatic cancer mouse model, mutant p53 can directly bind to p73, preventing p73-mediated inactivation of PDGFβ, driving an invasive and metastatic phenotype (52).”
BackgroundNagarajan, A. G., Dogra, S. K., Sun, L., Gandotra, N., Ho, T., Cai, G., Cline, G. W., Kumar, P., Cowles, R. A., & Wajapeyee, N. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.07.014 · Cited by 145 · see citing works
“Previous studies have shown that oncogenic KRAS mutations are necessary to initiate and maintain PDAC tumor growth (Bryant et al., 2014; Ying et al., 2012), and p53 mutations facilitate the metastatic progression of PDAC (Weissmueller et al., 2014).”
BackgroundInfluentialThe proprotein convertase furin in tumour progression
Jaaks, P., & Bernasconi, M. (2017) · International Journal of Cancer · doi:10.1002/ijc.30714 · Cited by 144 · see citing works
“Furthermore, autocrine PDGF signalling increases the metastatic potential of breast cancer and pancreatic cancer cells.(97,98) In diverse studies it has been shown that class III semaphorins are cleaved by furin or furin-like PCs, sometimes at multiple sites, however, the functional consequences of the processing step…”
BackgroundPfister, N. T., Fomin, V., Regunath, K., Zhou, J. Y., Zhou, W., Silwal‐Pandit, L., Freed-Pastor, W. A., Laptenko, O., Neo, S. P., Bargonetti, J., et al. (2015) · Genes & Development · doi:10.1101/gad.263202.115 · Cited by 143 · see citing works
“Interestingly, mutant p53 has been reported to stimulate additional receptor tyrosine kinases, including EGFR (Ludes-Meyers et al. 1996), IGF1R (Werner et al. 1996), MET (Muller et al. 2013), and PDGFRB (Weissmueller et al. 2014), all of which, along with VEGFR2, promote proproliferative signaling.”
BackgroundInfluentialSelf-citationPlatelet‐derived growth factor ( PDGF ) signalling in cancer: rapidly emerging signalling landscape
Farooqı, A. A., & Siddik, Z. H. (2015) · Cell Biochemistry and Function · doi:10.1002/cbf.3120 · Cited by 141 · see citing works
“Interestingly, the frequently occurring gain-of-function p53R172H and p53R273H mutants even induce PDGFRB, which may further promote the aggressive nature of such cancers.(4) Similarly, the p53 family member p73 can exist in the ΔNp73 isoform, which has been demonstrated in neuroblastoma to replace wild-type p53 on th…”
BackgroundEnhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1
Fang, L., Du, W. W., Lyu, J., Dong, J., Zhang, C., Yang, W., He, A. T., Kwok, Y. S. S., Ma, J., Wu, N., et al. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0115-6 · Cited by 139 · see citing works
“It has been known that the p53 mutant cells express much higher levels of the mutant p53 [33].”
Amelio, I., Mancini, M., Petrova, V., Cairns, R. A., Вихрева, П. Н., Nicolai, S., Marini, A., Antonov, A. A., Quesne, J. P. C. L., Acevedo, J. D. B., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1808314115 · Cited by 139 · see citing works
How mutations shape p53 interactions with the genome to promote tumorigenesis and drug resistance
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Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53Preprint
Pfister, N. T., & Prives, C. L. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026054 · Cited by 139 · see citing works
“…2008; Lim et al. 2009), which can be mediated through mutant p53 interaction with Ets-2 (Do et al. 2012), increased migration (Adorno et al. 2009; Weissmueller et al. 2014), increased invasion through Matrigel (Muller et al. 2009, 2013), increased tumor inflammation (Scian et al. 2005), and…”
BackgroundInfluentialSelf-citationHashimoto, S., Furukawa, S., Hashimoto, A., Tsutaho, A., Fukao, A., Sakamura, Y., Parajuli, G., Onodera, Y., Otsuka, Y., Handa, H., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1901765116 · Cited by 149 · see citing works
“Thus, it was enigmatic as to why PDGFR overexpression was a risk factor of PDACs (14), although most PDACs already have the KRAS oncogene.”
BackgroundInfluentialThe Function of the Mutant p53-R175H in Cancer
Chiang, Y.-T., Chien, Y., Lin, Y., Wu, H.-H., Lee, D., & Yu, Y. (2021) · Cancers · doi:10.3390/cancers13164088 · Cited by 118 · see citing works
“Pancreatic cancer p73 NF-YA, NF-YB, and NF-YC complex/PDGFRb [28]”
BackgroundInfluentialMaddalena, M., Mallel, G., Nataraj, N. B., Shreberk‐Shaked, M., Hassin, O., Mukherjee, S., Arandkar, S., Rotkopf, R., Kapsack, A., Lambiase, G., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2025631118 · Cited by 114 · see citing works
“For example, mutp53 can promote PDAC metastatic propensity by elevating the expression of platelet-derived growth factor receptor b (PDGFRb), which is achieved through the ability of mutp53 to bind and inhibit the p53-related p73 protein (51).”
BackgroundMutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5
Vogiatzi, F., Brandt, D. T., Schneikert, J., Fuchs, J., Grikscheit, K., Wanzel, M., Pavlakis, E., Charles, J. P., Timofeev, O., Nist, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612711114 · Cited by 99 · see citing works
“In part, this is achieved by mutp53 transcriptionally up-regulating the expression of receptors (20), by suppressing receptor targeting miRNAs (40), or by enhancing receptor recycling (18, 21).”
BackgroundInfluentialGong, Z., Zhang, S., Zeng, Z., Wu, H., Yang, Q., Xiong, F., Shi, L., Yang, J., Zhang, W., Zhou, Y., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110674 · Cited by 110 · see citing works
“p53 participates in all steps of tumor initiation and development by regulating the expression of many downstream genes; thus, p53 is also an important candidate target for cancer gene therapy [16, 17].”
BackgroundWu, K., Zhang, X., Li, F., Xiao, D., Hou, Y., Zhu, S., Liu, D., Ye, X., Ye, M., Yang, J., et al. (2015) · Nature Communications · doi:10.1038/ncomms10131 · Cited by 109 · see citing works
Mutant p53 controls tumor metabolism and metastasis by regulating PGC-1αPreprint
Basu, S., Gnanapradeepan, K., Barnoud, T., Kung, C.-P., Tavecchio, M., Scott, J., Watters, A. K., Chen, Q., Kossenkov, A. V., & Murphy, M. E. (2018) · Genes & Development · doi:10.1101/gad.309062.117 · Cited by 109 · see citing works
“Inactivation of p73 bymutant p53 causes increased PDGF receptor β (PDGFRβ) signaling and metastasis (Weissmueller et al. 2014).”
BackgroundMutant p53: Multiple Mechanisms Define Biologic Activity in Cancer
Kim, M., Zhang, Y., & Lozano, G. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00249 · Cited by 108 · see citing works
“Mutant p53-dependent sequestration of p73 from an NF-Y complex permits this transcriptional complex to function at the platelet-derived growth factor β promoter, resulting in expression of PDGFRβ and a prometastatic phenotype (41).”
BackgroundClinical implications of miRNAs in the pathogenesis, diagnosis and therapy of pancreatic cancer
Rachagani, S., Macha, M. A., Heimann, N., Seshacharyulu, P., Haridas, D., Chugh, S., & Batra, S. K. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.10.020 · Cited by 106 · see citing works
“However, p53 can also have gain of function mutations that can increase cell proliferation and other tumorigenic traits; in this case miRNA against p53 can have beneficial effects [65,194,195].”
HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer
Stojanovic, N., Hassan, Z., Wirth, M., Wenzel, P., Beyer, M., Schäfer, C., Brand, P., Kroemer, A., Stauber, R. H., Schmid, R. M., et al. (2016) · Oncogene · doi:10.1038/onc.2016.344 · Cited by 106 · see citing works
Gain-of-Function (GOF) Mutant p53 as Actionable Therapeutic Target
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NF-Y in cancer: Impact on cell transformation of a gene essential for proliferation
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Alexandrova, E. M., Mirza, S. A., Xu, S., Schulz‐Heddergott, R., Marchenko, N. D., & Moll, U. M. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.80 · Cited by 103 · see citing works
“In allografts, knockdown of mutp53 in Kras pancreatic cancer cells strongly reduces their metastatic ability.(9) Finally, in a conditional inactivatable (‘floxable’) autochthonous mouse model, ablation of the R248Q knockin allele extends survival by 37%, induces regression or stagnation of advanced tumors and strongly…”
BackgroundTargeting PDGF‐mediated recruitment of pericytes blocks vascular mimicry and tumor growth
Thijssen, V. L., Paulis, Y. W. J., Nowak-Sliwinska, P. M., Deumelandt, K., Hosaka, K., Soetekouw, P. M. M. B., Cîmpean, A. M., Raica, M., Pauwels, P., van den Oord, J. J., et al. (2018) · The Journal of Pathology · doi:10.1002/path.5152 · Cited by 103 · see citing works
“These findings extend the observations that interfering with PDGF signaling could provide therapeutic benefit for different cancer patients [36]; for example, for the treatment of patients with aggressive tumors that are refractory to angiostatic therapy.”
BackgroundTAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation
Amelio, I., Inoue, S., Markert, E. K., Levine, A. J., Knight, R. A., Mak, T. W., & Melino, G. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410609111 · Cited by 103 · see citing works
“Expression of mutant p53 disrupts the p73/NF-Y interaction, determining a PDGFRb-dependent metastatic potential of pancreatic cancer cells (27).”
BackgroundSelf-citationP53: A Guardian of Immunity Becomes Its Saboteur through Mutation
Agupitan, A. D., Neeson, P. J., Williams, S., Howitt, J. A., Haupt, S., & Haupt, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103452 · Cited by 109 · see citing works
“Moreover, Arf6 activation is facilitated by the platelet-derived growth factor (PDGF), a product of TLR4 signalling, and its β receptor (PDGFRβ), a direct target of mutant p53 [178,186,187].”
BackgroundNAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity
Li, Q., Liu, X., Jin, K., Lu, M., Zhang, C., Du, X., & Xing, B. (2017) · BMC Cancer · doi:10.1186/s12885-017-3570-4 · Cited by 98 · see citing works
Kong, B., Wu, W., Cheng, T., Schlitter, A. M., Qian, C., Bruns, P., Jian, Z., Jäger, C., Regel, I., Raulefs, S., et al. (2015) · Gut · doi:10.1136/gutjnl-2014-307616 · Cited by 97 · see citing works
Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine
Conway, J. R. W., Herrmann, D., Evans, T. J., Morton, J. P., & Timpson, P. (2018) · Gut · doi:10.1136/gutjnl-2018-316822 · Cited by 93 · see citing works
“42 145 146 Interest-ingly, one patient with PDAC who responded well to AZD2014 therapy in a phase I trial was found to have a PDGFR1A mutation, and this may present a novel biomarker for therapies aimed at PI3K pathway inhibition.”
Targeting the Oncogenic p53 Mutants in Colorectal Cancer and Other Solid Tumors
Li, H., Zhang, J., TONG, J. H. M., Chan, A. W. H., Yu, J. Q., Kang, W., & To, K. F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20235999 · Cited by 96 · see citing works
“Blocking of PDGFR-β prevents cancer cell invasion and metastasis formation both in vitro and in vivo [63].”
BackgroundCell fate regulation governed by p53: Friends or reversible foes in cancer therapy
Song, B., Yang, P., & Zhang, S. (2024) · 癌症：英文版 · doi:10.1002/cac2.12520 · Cited by 97 · see citing works
Do Mutations Turn p53 into an Oncogene?
Pitolli, C., Wang, Y., Mancini, M., Shi, Y., Melino, G., & Amelio, I. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20246241 · Cited by 95 · see citing works
“In pancreatic cancer, mutant R172H p53 has been shown to interact with p73, blocking the interaction of p73 with NF-Y (nuclear transcription factor Y), which in turn induces the expression of PDGFRβ (platelet-derived growth factor receptor beta), which is important for maintaining a metastatic phenotype (Figure 2A) [9…”
BackgroundHuang, Y., Liu, N., Liu, J., Liu, Y., Zhang, C., Long, S., Luo, G., Zhang, L., & Zhang, Y. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1688951 · Cited by 94 · see citing works
“A murine model data of pancreatic cancer harboring a latent mutant p53-R175H have firmly established that mutant p53 promoted invasion and metastasis through activating cell-autonomous PDGF receptor β Signaling [28].”
BackgroundHitting cancers’ weak spots: vulnerabilities imposed by p53 mutation
Gurpinar, E., & Vousden, K. H. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.04.001 · Cited by 94 · see citing works
Liu, G., Wei, C., Yuan, S., Zhang, Z., Li, J., Zhang, L., Wang, G., & Fang, L. (2022) · Phytotherapy Research · doi:10.1002/ptr.7558 · Cited by 93 · see citing works
Vidaurre, S., Fitzpatrick, C. J., Burzio, V. A., Briones, M., Villota, C., Villegas, J., Echenique, J., Oliveira-Cruz, L., Araya, M., Borgna, V., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.558841 · Cited by 93 · see citing works
Mutant p53: One, No One, and One Hundred Thousand
Walerych, D., Lisek, K., & Sal, G. D. (2015) · Frontiers in Oncology · doi:10.3389/fonc.2015.00289 · Cited by 92 · see citing works
“model and cell lines Metastasis Imatinib (22)”
BackgroundInfluentialHeterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?
Monti, P., Menichini, P., Speciale, A., Cutrona, G., Fais, F., Taìana, E., Neri, A., Bomben, R., Gentile, M., Gattei, V., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.593383 · Cited by 92 · see citing works
Loizou, E., Banito, A., Livshits, G., Ho, Y.-J., Koche, R. P., Sánchez-Rivera, F. J., Mayle, A., Chen, C.-C., Kinalis, S., Bagger, F. O., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1391 · Cited by 88 · see citing works
“For example, although p53R172H can display GOF effects by promoting invasion and metastasis in a pancreatic cancer model, it is not required for the sustained proliferation of pancreatic cancer cells, at least in vitro (13).”
BackgroundSelf-citationMutant p53 oncogenic functions in cancer stem cells are regulated by WIP through YAP/TAZ
Escoll, M., Gargini, R., Cuadrado, A., Anton, I. M., & Wandosell, F. G. (2017) · Oncogene · doi:10.1038/onc.2016.518 · Cited by 91 · see citing works
Chen, K., Qian, W., Li, J., Jiang, Z., Cheng, L., Yan, B., Cao, J., Sun, L., Zhou, C., Lei, M., et al. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12116 · Cited by 90 · see citing works
“Somatic mutations in the p53 tumor suppressor gene are also frequent genetic events that drive PDAC progression (Weissmueller et al., 2014).”
BackgroundZehendner, C. M., Valasarajan, C., Werner, A., Boeckel, J., Bischoff, F. C., John, D., Weirick, T., Glaser, S.-F., Roßbach, O., Jaé, N., et al. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201910-2041oc · Cited by 89 · see citing works
“It has previously been reported that p53 is a major regulator of PDGFRb and that it downregulates PDGFRb expression (42, 43); conversely, mutants of p53 have been found to drive PDGF signaling in various malignant diseases (44).”
BackgroundWang, W., Friedland, S. C., Guo, B., O'Dell, M. R., Alexander, W. B., Whitney-Miller, C. L., Agostini-Vulaj, D., Huber, A. R., Myers, J. R., Ashton, J., et al. (2018) · Gut · doi:10.1136/gutjnl-2017-315541 · Cited by 70 · see citing works
Furth, N., Aylon, Y., & Oren, M. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.163 · Cited by 87 · see citing works
Marquardt, S., Solanki, M., Spitschak, A., Vera, J., & Pützer, B. M. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.06.006 · Cited by 86 · see citing works
Agostino, S. D., Valenti, F., Sacconi, A., Fontemaggi, G., Pallocca, M., Pulito, C., Ganci, F., Muti, P. C., Strano, S., & Blandino, G. (2018) · Theranostics · doi:10.7150/thno.22167 · Cited by 83 · see citing works
“To further validate the analysis performed in TGCA subgroups, we considered PDGFRB as a gene transcriptionally regulated by mutant p53 [46] and MDM2 as a bona-fide target of wild-type p53.”
Siolas, D., Vucic, E., Kurz, E., Hajdu, C. H., & Bar‐Sagi, D. (2020) · Cell Reports · doi:10.1016/j.celrep.2021.109578 · Cited by 82 · see citing works
“Neutrophil presence (Chao et al., 2016; Steele et al., 2016) and Trp53R172H gain-of-function mutation in tumor cells (Morton et al., 2010; Weissmueller et al., 2014) have been implicated independently in promoting metastasis in mouse models of PDAC.”
BackgroundLi, P., Zhang, D., Shen, L., Dong, K., Wu, M., Ou, Z., & Shi, D. (2016) · Scientific Reports · doi:10.1038/srep22831 · Cited by 81 · see citing works
Wadhwa, R., Nigam, N., Bhargava, P., Dhanjal, J. K., Goyal, S., Grover, A., Sundar, D., Ishida, Y., Terao, K., & Kaul, S. C. (2016) · Journal of Cancer · doi:10.7150/jca.15170 · Cited by 81 · see citing works
“It is a complex multi-step phenomenon and involves interplay of several factors that enable cancer cells to acquire invasiveness and intravasate into circulatory system, survive in the blood or lymph circulation, form microvasculature and extravasate to form tumor mass at distant organs [1-3].”
BackgroundMolecularly targeted therapies for p53-mutant cancers
Zhao, D., Tahaney, W. M., Mazumdar, A., Savage, M. I., & Brown, P. H. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2575-0 · Cited by 81 · see citing works
“A recent study demonstrated that PDGFRb signaling enhanced the expression of a GOF mutant p53 induced pancreatic cancer metastasis in PKC mice harboring one oncogenic allele of Kras and one allele of p53 [146].”
Bioinformatics analysis of the serine and glycine pathway in cancer cells
Antonov, A. V., Agostini, M., Morello, M., Minieri, M., Melino, G., & Amelio, I. (2014) · Oncotarget · doi:10.18632/oncotarget.2668 · Cited by 80 · see citing works
“Part of mp53 GOF is due to mp53 interaction and consequent repression of the siblings, p63/p73 [78–81], making this scenario much more complex.”
BackgroundEZH2 cooperates with gain‐of‐function p53 mutants to promote cancer growth and metastasis
Zhao, Y., Ding, L., Wang, D., Ye, Z., He, Y., Ma, L., Zhu, R., Pan, Y., Wu, Q., Pang, K., et al. (2019) · The EMBO Journal · doi:10.15252/embj.201899599 · Cited by 78 · see citing works
“Given that mutated p53 proteins are generally considered less drug-gable (Lehmann & Pietenpol, 2012), endeavor has been largely focused on targeting the downstream effectors of each individual GOF mutant of p53 (Adorno et al , 2009; Weissmueller et al , 2014; Zhu et al , 2015).”
Human MYC G-quadruplex: From discovery to a cancer therapeutic target
Wang, W., Hu, S., Gu, Y., Yan, Y., Stovall, D. B., Li, D., & Sui, G. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188410 · Cited by 77 · see citing works
- 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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