Context Matters: NOTCH Signatures and Pathway in Cancer Progression and Metastasis

Abstract

The Notch signaling pathway is a critical player in embryogenesis but also plays various roles in tumorigenesis, with both tumor suppressor and oncogenic activities. Mutations, deletions, amplifications, or over-expression of Notch receptors, ligands, and a growing list of downstream Notch-activated genes have by now been described for most human cancer types. Yet, it often remains unclear what may be the functional impact of these changes for tumor biology, initiation, and progression, for cancer therapy, and for personalized medicine. Emerging data indicate that Notch signaling can also contribute to increased aggressive properties such as invasion, tumor heterogeneity, angiogenesis, or tumor cell dormancy within solid cancer tissues; especially in epithelial cancers, which are in the center of this review. Notch further supports the “stemness” of cancer cells and helps define the stem cell niche for their long-term survival, by integrating the interaction between cancer cells and the cells of the tumor microenvironment (TME). The complexity of Notch crosstalk with other signaling pathways and its roles in cell fate and trans-differentiation processes such as epithelial-to-mesenchymal transition (EMT) point to this pathway as a decisive player that may tip the balance between tumor suppression and promotion, differentiation and invasion. Here we not only review the literature, but also explore genomic databases with a specific focus on Notch signatures, and how they relate to different stages in tumor development. Altered Notch signaling hereby plays a key role for tumor cell survival and coping with a broad spectrum of vital issues, contributing to failed therapies, poor patient outcome, and loss of lives.

Circular RNAs: Emerging Regulators of the Major Signaling Pathways Involved in Cancer Progression

“…However, cases of late relapses and late mortality have increased as well, rendering the invasive potential and the formation of early metastasis major challenges that need to be confronted [ 9 , 11 ]. The progression of cancer is a complex multistep process that is not sufficiently understood, and is associated with increased clinical aggressiveness; therefore, it is difficult to be prevented or controlled [ 12 ]. For these reasons, it is imperative to further explore the genetic mechanisms underlying cancer progression, and circular RNAs (circRNAs) have emerged as key molecules in this context that interact multifariously with major signaling pathways.…”

Gastroblastoma with a novel EWSR1‐CTBP1 fusion presenting in adolescence

“…The NOTCH signaling pathway is critical for modulating cell‐cell interactions; alterations in NOTCH function have been implicated in a variety of different tumor types 22 . CTBP1 is a known corepressor of NOTCH signaling 23 .…”

Molecular Landscape of Vulvar Squamous Cell Carcinoma

“…Interestingly, the largest NGS cohort [33] identified significant rates of NOTCH-1 mutations in HPV-independent tumors (19%). The Notch signaling pathway is known as one of the key players in maintaining normal tissue homeostasis [46], but similarly to the PIK3CA/AKT/mTOR pathway, its prognostic and therapeutic implications are far from clear in solid cancers. Interestingly, high rates (71%) of NOTCH-1 mutations have been shown in a whole-exome sequencing study of squamous cell carcinomas of the penis [47], a male tumor with many similarities with VSCC (dual HPV-associated/HPV-independent pathway, similar precursor lesions).…”