Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling

Weissmueller, Susann; Manchado, Eusebio; Saborowski, Michael; Morris, John P.; Wagenblast, Elvin; Davis, Carrie A.; Moon, Sung-Hwan; Pfister, Neil T.; Tschaharganeh, Darjus F.; Kitzing, Thomas; Aust, Daniela E.; Markert, Elke; Wu, Jianmin; Grimmond, Sean M.; Pilarsky, Christian; Prives, Carol; Biankin, Andrew V.; Lowe, Scott W.

doi:10.1016/j.cell.2014.01.066

Cited by 418 publications

(375 citation statements)

References 57 publications

Supporting

Mentioning

359

Contrasting

Order By: Relevance

“…TP53 mutations are frequent mutational events in 75% of pancreatic adenocarcinoma that occur at the transition from benign pancreatic intraepithelial neoplasias to highly aggressive, invasive, and metastatic pancreatic ductal adenocarcinomas (PDAC) (20). Consistent with mutp53 driving invasion and metastatic progression, p53 accumulation in human PDAC significantly correlates with lymph node metastasis, and mice harboring pancreatic cancers driven by oncogenic Kras and the GOF mutant Trp53 R172H allele show more metastases compared with mice harboring a Trp53 null allele (26).…”

Section: Resultsmentioning

confidence: 86%

“…Among the novel mutp53-regulated genes, we noted ENTPD5, a UDPase that promotes the calnexin/calreticulinmediated folding of glycoproteins in the ER (22). As RTKs involved in cell proliferation, growth, and oncogenesis, including EGFR, MET, and PDGFRB, are the most heavily N-glycosylated receptors (25), and also decisive mediators of the prometastatic activity of mutp53 (18,20,21), we hypothesized that the ER-resident UDPase ENTPD5, which drives the calnexin/calreticulin cycle, might be a crucial downstream target of the mutp53 GOF.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, mutp53 has a broad effect on gene expression profiles by binding genes indirectly through interactions with other transcription factors; for example p63/p73, Sp1/Sp3, NF-Y, ETS2, vitamin D receptor, or SREBP2 (4), and by regulating chromatin-modifying enzymes such as the ATP-dependent nucleosome remodeling complex SWI/SNF and the histone H3 lysine 4 methyltransferases MLL1 and MLL2 (14,16,17). By increasing the expression of various receptor tyrosine kinases (RTKs), such as transforming growth factor β (TGFβ) receptor, epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (HGFR/c-MET), and plateletderived growth factor (PDGF) receptor β, mutp53 enhances proinvasive signaling, which is further reinforced by stimulatory effects of mutp53 on integrin/RCP-driven receptor recycling (18)(19)(20)(21).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Vogiatzi

Brandt

Schneikert

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5′-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.M utations in the TP53 tumor suppressor gene are the most frequent genetic alterations in human cancer and commonly compromise the gene's tumor suppressor activity. p53-knockout mice succumb to tumors very early in life, arguing that the loss of function associated with p53 mutations is sufficient on its own to explain the high mutation frequency observed in patients with cancer (1). However, in striking contrast to mutations in other tumor suppressor genes, the vast majority of TP53 gene alterations in patients with cancer neither ablate p53 expression nor produce unstable or truncated proteins. Instead, p53 mutations are mostly missense mutations resulting in expression of mutant p53 (mutp53) proteins with only single-amino acid substitutions that accumulate to steady-state levels greatly exceeding those of wild-type p53 (wtp53) in normal tissues. Immunohistochemical positivity for p53 is therefore considered a diagnostic marker for the presence of a TP53 mutation (2). The high prevalence of missense mutations suggests a selective advantage during cancer progression, so it was hypothesized early on in p53 research that p53 mutations are neomorphic and endow the mutp53 protein with novel oncogenic functions that actively promote cancer progression and therapy resistance (2). These oncogenic properties are generally referred to as the mutp53 gain of function (GOF).Over the years, substantial experimental evidence for mutp53 GOF has accumulated (3-5). For example, mice expressing cancer-associated p53 hot spot mutations from the endogenous Trp53 gene locus are remarkably different from p53-deficient mice: tumorigenesis is accelerated, and the spectrum of tumors is shifted toward carcinomas and more meta...

show abstract

Section: Resultsmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Vogiatzi

Brandt

Schneikert

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Interacting with nuclear factor Y (NF-Y), p73 represses the expression of platelet-derived growth factor receptor beta (PDGFRb) in pancreatic noninvasive cells. Expression of mutant p53 disrupts the p73/NF-Y interaction, determining a PDGFRb-dependent metastatic potential of pancreatic cancer cells (27). Our data and DAPI (blue) indicated intratumoral vascularization in shCTR-H1299-derived or shTAp73-H1299-derived tumor xenograft tissues.…”

Section: Tap73 Predicts Lung Adenocarcinoma Patient Survival and Corrmentioning

confidence: 92%

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

Amelio

Inoue

Markert

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

100

View full text Add to dashboard Cite

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activation are associated with cancer progression. Here, we demonstrate that the transcription factor TAp73 opposes HIF-1 activity through a nontranscriptional mechanism, thus affecting tumor angiogenesis. TAp73-deficient mice have an increased incidence of spontaneous and chemically induced tumors that also display enhanced vascularization. Mechanistically, TAp73 interacts with the regulatory subunit (α) of HIF-1 and recruits mouse double minute 2 homolog into the protein complex, thus promoting HIF-1α polyubiquitination and consequent proteasomal degradation in an oxygen-independent manner. In human lung cancer datasets, TAp73 strongly predicts good patient prognosis, and its expression is associated with low HIF-1 activation and angiogenesis. Our findings, supported by in vivo and clinical evidence, demonstrate a mechanism for oxygen-independent HIF-1 regulation, which has important implications for individualizing therapies in patients with cancer.

show abstract

“…21 Moreover, although mutations in TP73 are less frequent in human cancers than those of TP53, genetic aberrations of TP73 were reported in pancreatic cancer and correlated with patient outcome. 22 Based on the known impact of p53 in human and mouse models of PDA, 23 and on the potential role of TAp73 in inflammation and cancer crosstalk, 24 we wished to deepen our knowledge of TAp73 roles and functions in PDA.…”

mentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

show abstract

Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling

Cited by 418 publications

References 57 publications

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5

TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Contact Info

Product

Resources

About