Abstract
The evolutionarily-conserved Notch signaling pathway plays critical roles in cell communication, function and homeostasis equilibrium. The pathway serves as a cell-to-cell juxtaposed molecular transducer and is crucial in a number of cell processes including cell fate specification, asymmetric cell division and lateral inhibition. Notch also plays critical roles in organismal development, homeostasis, and regeneration, including somitogenesis, left-right asymmetry, neurogenesis, tissue repair, self-renewal and stemness, and its dysregulation has causative roles in a number of congenital and acquired pathologies, including cancer. In the lung, Notch activity is necessary for cell fate specification and expansion, and its aberrant activity is markedly linked to various defects in club cell formation, alveologenesis, and non-small cell lung cancer (NSCLC) development. In this review, we focus on the role this intercellular signaling device plays during lung development and on its functional relevance in proximo-distal cell fate specification, branching morphogenesis, and alveolar cell determination and maturation, then revise its involvement in NSCLC formation, progression and treatment refractoriness, particularly in the context of various mutational statuses associated with NSCLC, and, lastly, conclude by providing a succinct outlook of the therapeutic perspectives of Notch targeting in NSCLC therapy, including an overview on prospective synthetic lethality approaches.
Highlights
Notch signaling is a highly-conserved, cell-to-cell communication pathway serving several functions during mammalian lung development, including regulation of cell differentiation, survival, and lineage specification [1,2]
While normal Notch signaling is necessary for maintaining homeostasis, its aberrant activity has been shown to be implicated in the onset and progression of lung carcinomas, including non-small cell lung cancer (NSCLC) [10,11,12,13], where it, may serve of prognostic value [14,15], and as a predictor for therapy response and tumor recurrence [15,16,17]
Using Shh-Cre;Jag1flox/flox;Jag2flox/flox mice, the Cardoso group was able to demonstrate that the deficiency of Jagged ligands—which were shown in this study to be expressed in a proximo-distal wave pattern in the lung epithelium—did not result in marked alterations in neuroendocrine cells and bodies (NEB)’ distribution, Cgrp expression, or cluster extent size in the intrapulmonary airways, while Shh-Cre;Dll1flox/flox;Dll4flox/flox animals displayed marked enlargement of Ascl1+ neuroendocrine cell pool, which, was further modestly seen in animals conditionally deficient for Dll1 but not in ones for Dll4, markedly suggesting that while Dll1 is the main Notch ligand responsible for suppression of neuroendocrine fate in the developing epithelium, functional redundancy between these ligands exists in the control of neuroendocrine cell fate specification [54]
Summary
Notch signaling is a highly-conserved, cell-to-cell communication pathway serving several functions during mammalian lung development, including regulation of cell differentiation, survival, and lineage specification [1,2]. We first start by providing a deep mechanistic overview of Notch function in lung development and its driving role in the dynamics of lung cell populations’ ontogeny, fate decisions, and differentiation processes, as this fundamental mechanics seems evident that is well conserved in the molecular and cellular dynamics triggering lung cancer initiation and neoplastic progression, provide a conceptualized revision of Notch’s involvement in NSCLC formation and progression, in attention to the tumor promoter and/or suppressive roles of distinct Notch receptors, ligands and key regulators, and within the contexts of diverse cell ontogeny and fate choice selection, dynamic interplay interactions with other pathways, mutational status, genetic and epigenetic regulation, and on their potential as actionable drivers in disease progression and as targets for therapy, and, include a concise discussion on prospective Notch targeting therapies, subclinical and clinical testing studies, and on how these strategies could be integrated for synthetic lethality approaches and other combinational modalities
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