Molecular Profiling of the Developing Lacrimal Gland Reveals Putative Role of Notch Signaling in Branching Morphogenesis

Dvoriantchikova, Galina; Tao, Wensi; Pappas, Steve; Gaidosh, Gabriel; Tse, David T.; Ivanov, Dmitry; Pelaez, Daniel

doi:10.1167/iovs.16-20315

Cited by 15 publications

(17 citation statements)

References 37 publications

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“…Inhibition of Notch signaling reduces the average size of lobules, but increases the average number of lobules in the lacrimal gland indicating that Notch signaling controls branching morphogenesis in lacrimal glands. 31 In conjunction with previous reports that Notch prevents progenitor cell differentiation in mammary gland among other tissue types, it is likely that overactive Notch signaling in lacrimal glands contributes to dedifferentiation and changes in morphogenesis. With limitations in this study of a relatively small sample size and preliminary functional analysis, the study results suggest that the Notch pathway could play a key role in LGACC initiation and progression, thus suggesting a potential therapeutic target for LGACC.…”

Section: Discussionmentioning

confidence: 59%

Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma

Sant

Tao

Field

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeTo identify genomic mutations in lacrimal gland adenoid cystic carcinoma (LGACC) samples from patients.MethodsGenomic DNA was extracted from LGACC specimens. Whole exome sequencing (exome-seq) was conducted to screen for mutations. Capillary sequencing was performed to verify mutations in genes shared by multiple samples. Luciferase assays were used to evaluate functional consequences of NOTCH1 mutations.ResultsThe mutation profile of LGACC was complicated. The most frequently mutated gene observed (28.6%) was bromodomain PHD finger transcription factor (BPTF). No mutation was identified in common cancer genes such as TP53, KRAS, and BRAF. However, mutations predicted to be functionally severe were accumulated in the Notch signaling pathway including NOTCH1 and NOTCH2, of which mutations have been reported in head/neck adenoid cystic carcinoma (ACC). Of 14 LGACC samples, five samples carry mutations in Notch pathway genes. Capillary sequencing verified all the mutations in the two NOTCH genes identified by exome-seq. Compared to the wild-type NOTCH1, three frame shifting mutations and two missense mutations (C387W and L1600Q) increased luciferase activity approximately 10- to 25-fold.ConclusionsMajor genomic mutation profiles in LGACC were uncovered by exome-seq. Although preliminary in nature, the Notch pathway could be a potential therapeutic target for LGACC.

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Section: Discussionmentioning

confidence: 59%

Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma

Sant

Tao

Field

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Several signaling pathways are involved in LG morphogenesis and branching regulation (Makarenkova et al, 2000 ; Dean et al, 2004 ; Tsau et al, 2011 ; Chen et al, 2014 ). Among them, the Notch signaling regulatory network has recently been implicated in early mouse LG development (Dvoriantchikova et al, 2017 ). Moreover, for the first time, a recent report has demonstrated the implication of microRNAs activity in LG initiation, thus adding to the complex regulation of branched organs morphogenesis (Farmer et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Epithelial Markers aSMA, Krt14, and Krt19 Unveil Elements of Murine Lacrimal Gland Morphogenesis and Maturation

Kuony

Michon

2017

Front. Physiol.

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As an element of the lacrimal apparatus, the lacrimal gland (LG) produces the aqueous part of the tear film, which protects the eye surface. Therefore, a defective LG can lead to serious eyesight impairment. Up to now, little is known about LG morphogenesis and subsequent maturation. In this study, we delineated elements of the cellular and molecular events involved in LG formation by using three epithelial markers, namely aSMA, Krt14, and Krt19. While aSMA marked a restricted epithelial population of the terminal end buds (TEBs) in the forming LG, Krt14 was found in the whole embryonic LG epithelial basal cell layer. Interestingly, Krt19 specifically labeled the presumptive ductal domain and subsequently, the luminal cell layer. By combining these markers, the Fucci reporter mouse strain and genetic fate mapping of the Krt14+ population, we demonstrated that LG epithelium expansion is fuelled by a patterned cell proliferation, and to a lesser extent by epithelial reorganization and possible mesenchymal-to-epithelial transition. We pointed out that this epithelial reorganization, which is associated with apoptosis, regulated the lumen formation. Finally, we showed that the inhibition of Notch signaling prevented the ductal identity from setting, and led to a LG covered by ectopic TEBs. Taken together our results bring a deeper understanding on LG morphogenesis, epithelial domain identity, and organ expansion.

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“…The overview of natural products targeting MYB in LGACC is shown in Figure 5. Though not discussed here, Notch, Wnt, TGFβ, and Hh signaling are important pathways for EMT for LGACC as well [108]. …”

Section: Lacrimal Gland Adenocystic Carcinomamentioning

confidence: 99%

Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer

Zhang

Gallo

Tao

et al. 2018

Pharmacological Research

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Carcinogenesis has a multifactorial etiology, and the underlying molecular pathogenesis is still not entirely understood, especially for eye cancers. Primary malignant intraocular neoplasms are relatively rare, but delayed detection and inappropriate management contribute to poor outcomes. Conventional treatment, such as orbital exenteration, chemotherapy, or radiotherapy, alone results in high mortality for many of these malignancies. Recent sequential multimodal therapy with a combination of high-dose chemotherapy, followed by appropriate surgery, radiotherapy, and additional adjuvant chemotherapy has helped dramatically improve management. Transcription factors are proteins that regulate gene expression by modulating the synthesis of mRNA. Since transcription is a dominant control point in the production of many proteins, transcription factors represent key regulators for numerous cellular functions, including proliferation, differentiation, and apoptosis, making them compelling targets for drug development. Natural compounds have been studied for their potential to be potent yet safe chemotherapeutic drugs. Since the ancient times, plant-derived bioactive molecules have been used to treat dreadful diseases like cancer, and several refined pharmaceutics have been developed from these compounds. Understanding targeting mechanisms of oncogenic transcription factors by natural products can add to our oncologic management toolbox. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in various types of eye cancer.

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Molecular Profiling of the Developing Lacrimal Gland Reveals Putative Role of Notch Signaling in Branching Morphogenesis

Cited by 15 publications

References 37 publications

Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma

Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma

Epithelial Markers aSMA, Krt14, and Krt19 Unveil Elements of Murine Lacrimal Gland Morphogenesis and Maturation

Therapeutic targeting of oncogenic transcription factors by natural products in eye cancer

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