Akt Activation Synergizes with <i>Trp53</i> Loss in Oral Epithelium to Produce a Novel Mouse Model for Head and Neck Squamous Cell Carcinoma

Moral, Marta; Segrelles, Carmen; Lara, M. Fernanda; Martínez-Cruz, Ana Belén; Lorz, Corina; Santos, Mirentxu; García‐Escudero, Ramón; Lu, Jerry; Kiguchi, Kaoru; Buitrago, Agueda; Costa, Clotilde; Saiz, Cristina; Rodríguez-Peralto, José L.; Martínez‐Tello, Francisco J.; Rodríguez-Pinilla, María; Sanchez-Cespedes, Montse; Garín, Marina I.; Grande, Teresa; Bravo, Ana; DiGiovanni, John; Paramio, Jesús M.

doi:10.1158/0008-5472.can-08-3240

Cited by 52 publications

(50 citation statements)

References 44 publications

(74 reference statements)

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“…Similar to human SCC, these tumors also expressed robust levels of EGFR and cyclin D1 proteins (Supplemental Figure 1A; supplemental material available online with this article; doi:10.1172/JCI68899DS1), and resemble the recently described "classical SCC" that develops in carcinogentreated mice (27). Human SCCs frequently harbor inactivating mutations in p53 (2,3,28), and p53 inactivation is important for SCC progression in genetic models of oral SCC, cooperating potently with events such as AKT activation (29). Consistent with these data, we found that SCC tumors arising in DMBAtreated p53 +/-mice appeared at reduced latency compared with those occurring in WT mice ( Figure 1C) (30,31).…”

Section: Introductionmentioning

confidence: 68%

FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

Ramsey

Wilson²,

Ory³

et al. 2013

J. Clin. Invest.

100

101

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Oncogenic transcription factors drive many human cancers, yet identifying and therapeutically targeting the resulting deregulated pathways has proven difficult. Squamous cell carcinoma (SCC) is a common and lethal human cancer, and relatively little progress has been made in improving outcomes for SCC due to a poor understanding of its underlying molecular pathogenesis. While SCCs typically lack somatic oncogene-activating mutations, they exhibit frequent overexpression of the p53-related transcription factor p63. We developed an in vivo murine tumor model to investigate the function and key transcriptional programs of p63 in SCC. Here, we show that established SCCs are exquisitely dependent on p63, as acute genetic ablation of p63 in advanced, invasive SCC induced rapid and dramatic apoptosis and tumor regression. In vivo genome-wide gene expression analysis identified a tumor-survival program involving p63-regulated FGFR2 signaling that was activated by ligand emanating from abundant tumor-associated stroma. Correspondingly, we demonstrate the therapeutic efficacy of extinguishing this signaling axis in endogenous SCCs using the clinical FGFR2 inhibitor AZD4547. Collectively, these results reveal an unanticipated role for p63-driven paracrine FGFR2 signaling as an addicting pathway in human cancer and suggest a new approach for the treatment of SCC.

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Section: Introductionmentioning

confidence: 68%

FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

Ramsey

Wilson²,

Ory³

et al. 2013

J. Clin. Invest.

100

101

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“…Akt-induced senescence has been associated with the activation of TP53-dependent mechanisms (Chen et al ., 2005; Kim et al ., 2007). The results from a previous study suggested that TP53-mediated senescence was responsible for the reduced malignant conversion of oral lesions in mice displaying constitutive Akt activity (myrAkt) (Moral et al ., 2009). While the Western blot results revealed that TP53 was undetectable in association with increased p-Akt, we did detect an increase in the expression of the CDKN2D (p19Arf) gene.…”

Section: Resultsmentioning

confidence: 99%

Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation

Bian

Hall²,

Sun³

et al. 2011

Oncogene

151

186

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The molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been completely delineated. Our observations indicate that defects in the TGF-β and PI3K/Akt signaling pathways are common in human HNSCCs. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-β receptor (Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice. Furthermore, neoplastic transformation involves senescence evasion and is associated with an increased number of putative cancer stem cells (CSCs). In addition, the NF-κB pathway activation, myeloid derived suppressor cell (MDSC) infiltration, angiogenesis, and immune suppression in the tumor microenvironment, all of which are characteristic of human HNSCCs, contribute significantly to head and neck carcinogenesis in 2cKO mice. These tumors display pathology and multiple molecular alterations resembling human HNSCCs. This suggests that the Tgfbr1/Pten 2cKO mouse model is suitable for preclinical intervention, and that it has significant implications in the development of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs.

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“…Activation of AKT is one of the major mechanisms of tumorigenesis, and blocking this signaling pathway could have therapeutic implications for tumors. Previous studies demonstrated that the activation of AKT is associated with intrinsic radioresistance, tumor cell proliferation, and angiogenesis in vivo [27]. AKT can affect proliferation signaling and induce anti-apoptotic effects in tumors.…”

Section: Discussionmentioning

confidence: 99%

Salmonella inhibits tumor angiogenesis by downregulation of vascular endothelial growth factor

Chang

Lin

et al. 2016

Oncotarget

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Salmonella is a Gram-negative, facultative anaerobe that is a common cause of host intestinal infections. Salmonella grows under aerobic and anaerobic conditions, and it has been proven capable of inhibiting tumor growth. However, the molecular mechanism by which Salmonella inhibits tumor growth is still unclear. Angiogenesis plays an important role in the development and progression of tumors. We investigated the antitumor effect of Salmonella in a syngeneic murine tumor model. Hypoxia-inducible factor-1 (HIF-1)α plays a significant role in tumor angiogenesis. We examined the molecular mechanism by which Salmonella regulated vascular endothelial growth factor (VEGF), which is an important angiogenic factor. The expression of VEGF in tumor cells was decreased by treatment with Salmonella. The conditioned medium from Salmonella-treated cells inhibited the proliferation of endothelial cells. Salmonella inhibited the expression of HIF-1α as well as downregulated its upstream signal mediator protein kinase B (AKT). Salmonella significantly inhibited tumor growth in vivo, and immunohistochemical studies of the tumors revealed decreased intratumoral microvessel density. These results suggest that Salmonella therapy, which exerts anti-angiogenic activities, represents a promising strategy for the treatment of tumors.

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Akt Activation Synergizes with Trp53 Loss in Oral Epithelium to Produce a Novel Mouse Model for Head and Neck Squamous Cell Carcinoma

Cited by 52 publications

References 44 publications

FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

FGFR2 signaling underlies p63 oncogenic function in squamous cell carcinoma

Loss of TGF-β signaling and PTEN promotes head and neck squamous cell carcinoma through cellular senescence evasion and cancer-related inflammation

Salmonella inhibits tumor angiogenesis by downregulation of vascular endothelial growth factor

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