Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities

Kagawa, Shingo; Natsuizaka, Mitsuteru; Ka, Whelan; Facompre, Nicole D.; Naganuma, Seiji; Ohashi, Shinya; Kinugasa, Hideaki; Am, Egloff; Basu, Devraj; Gimotty, PA; Aj, Klein-Szanto; Aj, Bass; Wong, Kah Keng; Ja, Diehl; Ak, Rustgi; Nakagawa, Hiroshi

doi:10.1038/onc.2014.169

Cited by 60 publications

(74 citation statements)

References 63 publications

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“…(42, 43) NOTCH1 alterations can result in either tumor suppression or oncogenesis, depending on the tumor type. (44–46) Additional characterization of Notch signaling alterations in ACC is indicated, particularly because Notch signaling is a potentially targetable pathway. (42) Our findings also corroborate a high prevalence of somatic mutations in genes related to chromatin remodeling, including MLL2, MLL3, and EP300, among others.…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Rettig

Talbot

Sausen

et al. 2016

Cancer Prevention Research

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Adenoid cystic carcinomas (ACCs) of the salivary glands are challenging to understand, treat, and cure. To better understand the genetic alterations underlying the pathogenesis of these tumors, we performed comprehensive genome analyses of 25 fresh-frozen tumors, including whole genome sequencing, expression and pathway analyses. In addition to the well-described MYB-NFIB fusion which was found in 11 tumors (44%), we observed five different rearrangements involving the NFIB transcription factor gene in seven tumors (28%). Taken together, NFIB translocations occurred in 15 of 25 samples (60%, 95%CI=41–77%). In addition, mRNA expression analysis of 17 tumors revealed overexpression of NFIB in ACC tumors compared with normal tissues (p=0.002). There was no difference in NFIB mRNA expression in tumors with NFIB fusions compared to those without. We also report somatic mutations of genes involved in the axonal guidance and Rho family signaling pathways. Finally, we confirm previously described alterations in genes related to chromatin regulation and Notch signaling. Our findings suggest a separate role for NFIB in ACC oncogenesis and highlight important signaling pathways for future functional characterization and potential therapeutic targeting.

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Section: Discussionmentioning

confidence: 99%

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Rettig

Talbot

Sausen

et al. 2016

Cancer Prevention Research

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“…Activated NOTCH1 form more number of spheres as compared to vector control cells post 5 days (Supplementary Figure S6, S6C). However, given that AW13516 cells are HPV negative [25] and harbor wild-type p16INK4A and mutant Tp53 [23], ectopic expression of full-length NOTCH1 or NICD led to continuous cell death and senescence mediated growth arrest (Supplementary Figure S6, S6G), as described earlier [26-28]. …”

Section: Resultsmentioning

confidence: 65%

Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer

et al. 2016

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BackgroundNotch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC).Patients and MethodsWe analyzed the Notch signaling pathway in 68 early stage TSCC primary tumor samples by whole exome and transcriptome sequencing, real-time PCR based copy number, expression, immuno-histochemical, followed by cell based biochemical and functional assays.ResultsWe show, unlike TCGA HNSCC data set, NOTCH1 harbors significantly lower frequency of inactivating mutations (4%); is somatically amplified; and, overexpressed in 31% and 37% of early stage TSCC patients, respectively. HNSCC cell lines over expressing NOTCH1, when plated in the absence of attachment, are enriched in stem cell markers and form spheroids. Furthermore, we show that inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in TSCC. Clinically, Notch pathway activation is higher in tumors of non-smokers compared to smokers (50% Vs 18%, respectively, P=0.026) and is also associated with greater nodal positivity compared to its non-activation (93% Vs 64%, respectively, P=0.029).ConclusionWe anticipate that these results could form the basis for therapeutic targeting of NOTCH1 in tongue cancer.

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“…(32, 39) In fact, there is increasing support for a dual oncogenic and tumor suppressor role for Notch signaling within the same solid tumor type in several malignancies including breast, pancreatic, esophageal and NSCLC. (32, 40)…”

Section: Discussionmentioning

confidence: 99%

Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features

Rettig

Chung

Bishop

et al. 2015

Cancer Prevention Research

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The Notch pathway is frequently altered in HNSCCs, however the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 Intracellular Domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. Immunohistochemistry for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/non-peripheral (34%) and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (p<0.001). Most NOTCH1-wild type tumors were peripheral (55%), while mutated NOTCH1 tumors were most commonly negative (47%). Non-peripheral tumors were more likely than peripheral tumors to have extracapsular spread (aOR 16.01, 95% CI=1.92–133.46, p=0.010) and poor differentiation (aOR 5.27, 95% CI=0.90–30.86, p=0.066). Negative staining tumors tended to be poorly differentiated (aOR 24.71, 95% CI=1.53–399.33, p=0.024) and were less likely to be HPV-positive (aOR 0.043, 95% CI=0.001–1.59, p=0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV-positive than NOTCH1-mutated tumors (aOR 19.06, 95% CI=1.31–276.15, p=0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein.

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Cellular senescence checkpoint function determines differential Notch1-dependent oncogenic and tumor-suppressor activities

Cited by 60 publications

References 63 publications

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Whole-Genome Sequencing of Salivary Gland Adenoid Cystic Carcinoma

Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer

Cleaved NOTCH1 Expression Pattern in Head and Neck Squamous Cell Carcinoma Is Associated with NOTCH1 Mutation, HPV Status, and High-Risk Features

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