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"Palermo, Rocco"
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The Two-Way Role of Jagged1 in Cancer: A Focus on CRC
Colorectal cancer (CRC) remains one of the most prevalent and lethal malignancies. Accumulating genetic evidence supports a multistep model of tumor progression, in which early APC loss leads to chromosomal instability and adenoma formation, followed by activating mutations in KRAS that synergize with β-catenin signaling to promote tumor growth and invasion. Among the downstream effectors of these pathways, the Notch ligand Jagged1 has emerged as a critical mediator of CRC progression and chemoresistance. Jagged1 is not only a transcriptional target of the Wnt/β-catenin axis but also undergoes proteolytic cleavage via the KRAS/ERK/ADAM17 signaling cascade, generating a nuclear Jagged1 intracellular domain (Jag1-ICD) that drives reverse signaling. This dual functionality, activating canonical Notch signaling and initiating reverse nuclear signaling, positions Jagged1 as a key oncogenic driver in CRC. In this review, we first summarize the role of Jagged1 as an integral part of canonical Notch signaling. We then focus on the non-canonical Jagged1 reverse signaling function in cancer, with a particular emphasis on CRC. We underscore the dual role of Jagged1 in tumor biology and propose that it functions as a novel oncogene within the adenoma-to-carcinoma sequence, supporting CRC development and drug resistance via non-canonical mechanisms.
Journal Article
Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives
Notch signaling guides cell fate decisions by affecting proliferation, apoptosis, stem cell self-renewal, and differentiation depending on cell and tissue context. Given its multifaceted function during tissue development, both overactivation and loss of Notch signaling have been linked to tumorigenesis in ways that are either oncogenic or oncosuppressive, but always context-dependent. Notch signaling is critical for several mechanisms of chemoresistance including cancer stem cell maintenance, epithelial-mesenchymal transition, tumor-stroma interaction, and malignant neovascularization that makes its targeting an appealing strategy against tumor growth and recurrence. During the last decades, numerous Notch-interfering agents have been developed, and the abundant preclinical evidence has been transformed in orphan drug approval for few rare diseases. However, the majority of Notch-dependent malignancies remain untargeted, even if the application of Notch inhibitors alone or in combination with common chemotherapeutic drugs is being evaluated in clinical trials. The modest clinical success of current Notch-targeting strategies is mostly due to their limited efficacy and severe on-target toxicity in Notch-controlled healthy tissues. Here, we review the available preclinical and clinical evidence on combinatorial treatment between different Notch signaling inhibitors and existent chemotherapeutic drugs, providing a comprehensive picture of molecular mechanisms explaining the potential or lacking success of these combinations.
Journal Article
Identification of a novel chalcone derivative that inhibits Notch signaling in T-cell acute lymphoblastic leukemia
Notch signaling is considered a rational target in the therapy of several cancers, particularly those harbouring Notch gain of function mutations, including T-cell acute lymphoblastic leukemia (T-ALL). Although currently available Notch-blocking agents are showing anti-tumor activity in preclinical studies, they are not effective in all the patients and often cause severe side-effects, limiting their widespread therapeutic use. Here, by functional and biological analysis of the most representative molecules of an
in house
library of natural products, we have designed and synthetized the chalcone-derivative
8
possessing Notch inhibitory activity at low micro molar concentration in T-ALL cell lines. Structure-activity relationships were afforded for the chalcone scaffold. Short term treatments with compound
8
resulted in a dose-dependent decrease of Notch signaling activity, halted cell cycle progression and induced apoptosis, thus affecting leukemia cell growth. Taken together, our data indicate that
8
is a novel Notch inhibitor, candidate for further investigation and development as an additional therapeutic option against Notch-dependent cancers.
Journal Article
Prolyl-isomerase Pin1 drives platinum resistance by regulating Notch3 stability and function in ovarian cancer
Background
Resistance to platinum-based drugs represents a major obstacle for the management of high-grade serous ovarian cancer (HGSOC) patients. Indeed, the selective pressure of platinum-based (PT) chemotherapy often leads to the outgrowth of platinum-resistant subclones. In this scenario, the underlying adaptive networks should be fully investigated to provide advances toward more streamlined and personalized care.
Methods
We conducted a comprehensive analysis of Pin1/Notch3relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.We conducted a comprehensive analysis of relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.
Results
Here, we demonstrated that carboplatin treatment of HGSOC cells promoted the activation of the Pin1/Notch3 axis, resulting in platinum resistance. Accordingly, HGSOC-bearing patients showing increased Pin1/Notch3 co-expression after PT-based chemotherapy correlated with a clinical worse response. Conversely, genetic targeting of Pin1 combined with carboplatin treatment sensitizes resistant cells to platinum-based therapy, both in vitro and in vivo, strongly reducing their Notch3-mediated metastatic potential in preclinical murine models. Mechanistically, Pin1-Notch3 binding favours protection of Notch3 from its GSK3β-mediated degradation, resulting in increased Notch3 expression.
Conclusions
Collectively, our findings identify the functional Pin1/Notch3 axis as an escape strategy from chemotherapy-induced cell death, thus suggesting a novel predictive role of the Pin1/Notch3 axis in the platinum response, which could be useful for implementing frontline treatments for HGSOC patients before recurrence.
Journal Article
The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease
Mutation of the Golgi Ca
2+
-ATPase
ATP2C1
is associated with deregulated calcium homeostasis and altered skin function.
ATP2C1
mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified
ATP2C1
as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon
ATP2C1
inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR,
ATP2C1
inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an
ATP2C1/NOTCH1
axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease.
Journal Article
When Viruses Cross Developmental Pathways
Aberrant regulation of developmental pathways plays a key role in tumorigenesis. Tumor cells differ from normal cells in their sustained proliferation, replicative immortality, resistance to cell death and growth inhibition, angiogenesis, and metastatic behavior. Often they acquire these features as a consequence of dysregulated Hedgehog, Notch, or WNT signaling pathways. Human tumor viruses affect the cancer cell hallmarks by encoding oncogenic proteins, and/or by modifying the microenvironment, as well as by conveying genomic instability to accelerate cancer development. In addition, viral immune evasion mechanisms may compromise developmental pathways to accelerate tumor growth. Viruses achieve this by influencing both coding and non-coding gene regulatory pathways. Elucidating how oncogenic viruses intersect with and modulate developmental pathways is crucial to understanding viral tumorigenesis. Many currently available antiviral therapies target viral lytic cycle replication but with low efficacy and severe side effects. A greater understanding of the cross-signaling between oncogenic viruses and developmental pathways will improve the efficacy of next-generation inhibitors and pave the way to more targeted antiviral therapies.
Journal Article
CLIMATIC VARIATIONS AND IMPERIAL LANDSCAPES IN NORTHERN MESOPOTAMIA. FROM THE FALL OF ASSYRIA TO THE PARTHIAN-ROMAN PERIOD
This article discusses the relationship between urbanization and ruralization phenomena and the climatic oscillations in northern Mesopotamia from the end of Assyria to the Parthian-Roman period (7th c. BC – early 3rd c. AD). I employ data from the Erbil Plain Archaeological Survey (EPAS, Harvard) and the Land of Nineveh Archaeological Project (LoNAP, Udine), both projects operating in the Kurdistan Region of Iraq, to cross-correlate spatial patterns of urban and rural settlements, their evolution, contraction, and expansion, with paleoenvironmental records (speleothems) from the Gejkar cave and the Kuna Ba cave, located in roughly the same area. Moving away from a simply deterministic view, my paper suggests however the critical role of mutable climatic conditions in the ecologically fragile landscapes of North Mesopotamia and how such variations, coupled with political reliability or instability and the proximity or absence of a centralized authority, have played a major role in cycles of formation, expansion, and decline of territorial empires.
Journal Article
PKCθ mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia
Protein kinase (PK)C
θ
is a critical regulator of mature T-cell activation and proliferation, being implicated in TCR-triggered nuclear factor (NF)-
κ
B activation and providing important survival signals to leukemic T cells. We previously showed that overexpression of pT
α
/pre-TCR and constitutive activation of NF-
κ
B characterize the T-cell leukemia/lymphoma developing in Notch3-IC transgenic mice. We report here that PKC
θ
is a downstream target of Notch3 signaling and that its activation and membrane translocation require a functional pre-TCR in order to trigger NF-
κ
B activation in thymocytes and lymphoma cells of transgenic mice. Furthermore, deletion of PKC
θ
in Notch3-IC transgenic mice reduces the incidence of leukemia, correlating with decreased NF-
κ
B activation. This paper therefore suggests that PKC
θ
mediates the activation of NF-
κ
B by pre-TCR in immature thymocytes and contributes to the development of Notch3-dependent T-cell lymphoma.
Journal Article