Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity

Weaver, Alice N.; Burch, M. Benjamin; Cooper, Tiffiny S.; Manna, Deborah L. Della; Wei, Shi; Ojesina, Akinyemi I.; Rosenthal, Eben L.; Yang, Eddy S.

doi:10.1158/1541-7786.mcr-16-0114

Cited by 32 publications

(28 citation statements)

References 40 publications

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“…Early-stage clinical trials are investigating inhibition of notch through inhibition of g-secretase (the enzyme responsible for cleavage of notch receptors and downstream signaling) as a potential anticancer therapeutic strategy (34). It will be worth further investigating the exact role of NOTCH1 in the carcinogenesis in VC, as it might be a novel opportunity for targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

112

163

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Purpose: Vulvar cancer (VC) can be subclassified by human papillomavirus (HPV) status. HPV-negative VCs frequently harbor TP53 mutations; however, in-depth analysis of other potential molecular genetic alterations is lacking. We comprehensively assessed somatic mutations in a large series of vulvar (pre)cancers.Experimental Design: We performed targeted next-generation sequencing (17 genes), p53 immunohistochemistry and HPV testing on 36 VC and 82 precursors (sequencing cohort). Subsequently, the prognostic significance of the three subtypes identified in the sequencing cohort was assessed in a series of 236 VC patients (follow-up cohort).Results: Frequent recurrent mutations were identified in HPVnegative vulvar (pre)cancers in TP53 (42% and 68%), NOTCH1 (28% and 41%), and HRAS (20% and 31%). Mutation frequency in HPV-positive vulvar (pre)cancers was significantly lower (P ¼ 0.001). Furthermore, a substantial subset of the HPV-negative precursors (35/60, 58.3%) and VC (10/29, 34.5%) were TP53 wild-type (wt), suggesting a third, not-previously described, molecular subtype. Clinical outcomes in the three different subtypes (HPV þ , HPV À /p53wt, HPV À /p53abn) were evaluated in a follow-up cohort consisting of 236 VC patients. Local recurrence rate was 5.3% for HPV þ , 16.3% for HPV À /p53wt and 22.6% for HPV À /p53abn tumors (P ¼ 0.044). HPV positivity remained an independent prognostic factor for favorable outcome in the multivariable analysis (P ¼ 0.020).Conclusions: HPV À and HPV þ vulvar (pre)cancers display striking differences in somatic mutation patterns. HPV À /p53wt VC appear to be a distinct clinicopathologic subgroup with frequent NOTCH1 mutations. HPV þ VC have a significantly lower local recurrence rate, independent of clinicopathological variables, opening opportunities for reducing overtreatment in VC.

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Section: Discussionmentioning

confidence: 99%

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Nooij

Haar

Ruano

et al. 2017

Clinical Cancer Research

112

163

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“…In addition, Notch-mediated signalling is associated with the induction of EMT under hypoxic conditions in OSCC ( 57 ). It is also associated with high mortality and T classification in OSCC, as well as with an increase in cell migration and invasion ( 58 , 59 ).…”

Section: Discussionmentioning

confidence: 99%

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Rodrigues

Miguita²,

Andrade³

et al. 2018

Int J Oncol

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Oral squamous cell carcinoma (OSCC) is an extremely aggressive disease associated with a poor prognosis. Previous studies have established that cancer stem cells (CSCs) actively participate in OSCC development, progression and resistance to conventional treatments. Furthermore, CSCs frequently exhibit a deregulated expression of normal stem cell signalling pathways, thereby acquiring their distinctive abilities, of which self-renewal is an example. In this study, we examined the effects of GLI3 knockdown in OSCC, as well as the differentially expressed genes in CSC-like cells (CSCLCs) expressing high (CD44high) or low (CD44low) levels of CD44. The prognostic value of GLI3 in OSCC was also evaluated. The OSCC cell lines were sorted based on CD44 expression; gene expression was evaluated using a PCR array. Following this, we examined the effects of GLI3 knockdown on CD44 and ESA expression, colony and sphere formation capability, stem-related gene expression, proliferation and invasion. The overexpression of genes related to the Notch, transforming growth factor (TGF)β, FGF, Hedgehog, Wnt and pluripotency maintenance pathways was observed in the CD44high cells. GLI3 knockdown was associated with a significant decrease in different CSCLC fractions, spheres and colonies in addition to the downregulation of the CD44, Octamer-binding transcription factor 4 (OCT4; also known as POU5F1) and BMI1 genes. This downregulation was accompanied by an increase in the expression of the Involucrin (IVL) and S100A9 genes. Cellular proliferation and invasion were inhibited following GLI3 knockdown. In OSCC samples, a high GLI3 expression was associated with tumour size but not with prognosis. On the whole, the findings of this study demonstrate for the first time, at least to the best of our knowledge, that GLI3 contributes to OSCC stemness and malignant behaviour. These findings suggest the potential for the development of novel therapies, either in isolation or in combination with other drugs, based on CSCs in OSCC.

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“…Cell proliferation assays were performed as described previously ( 15 ). Briefly, cells were seeded in 24-well plates and harvested at 48, 72, and 96 hours after treatments.…”

Section: Methodsmentioning

confidence: 99%

Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma

Zeng

Beggs

Cooper

et al. 2017

Molecular Cancer Therapeutics

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EGFR inhibition and radiotherapy are potent inducers of DNA damage. Checkpoint kinases 1 and 2 (Chk1/2) are critical regulators of the DNA-damage response, controlling cell-cycle checkpoints that may permit recovery from therapy-associated genomic stress. We hypothesized that Chk1/2 inhibition (CHKi) with prexasertib may enhance cytotoxicity from EGFR inhibition plus radiotherapy in head and neck squamous cell carcinoma (HNSCC). In this study, we found that the addition of CHKi to the EGFR inhibitor cetuximab with and without radiotherapy significantly decreased cell proliferation and survival fraction in human papillomavirus virus (HPV)-positive and HPV-negative HNSCC cell lines. Reduced proliferation was accompanied by decreased checkpoint activation, induced S-phase accumulation, persistent DNA damage, and increased caspase cleavage and apoptosis. Importantly, a significant tumor growth delay was observed in vivo in both HPV-positive and HPV-negative cell line xenografts receiving triple combination therapy with CHKi, cetuximab, and radiotherapy without a concomitant increase in toxicity as assessed by mouse body weight. Taken together, the combination of CHKi with cetuximab plus irradiation displayed significant antitumor effects in HNSCCs both in vitro and in vivo, suggesting that this combination therapy may increase clinical benefit. A clinical trial to test this treatment for patients with head and neck cancer is currently ongoing (NCT02555644).

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Notch Signaling Activation Is Associated with Patient Mortality and Increased FGF1-Mediated Invasion in Squamous Cell Carcinoma of the Oral Cavity

Abstract: Oral squamous cell carcinoma (OSCC) is a cancer subtype that lacks validated prognostic and therapeutic biomarkers, and human papillomavirus status has not proven beneficial in predicting patient outcomes.

Cited by 32 publications

References 40 publications

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

Genomic Characterization of Vulvar (Pre)cancers Identifies Distinct Molecular Subtypes with Prognostic Significance

GLI3 knockdown decreases stemness, cell proliferation and invasion in oral squamous cell carcinoma

Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma

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