Notch signaling pathway in cancer: from mechanistic insights to targeted therapies

Abstract

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.

Fig. 1

Notch signaling overview. a Four Notch receptors (Notch1, Notch2, Notch3, and Notch4) and their respective structures. b Structures of five Notch ligands (JAG1, JAG2, DLL1, DLL3, and DLL4). c Schematic representation of canonical and non-canonical Notch signaling pathways. (Figure created using BioRender.com). NECD Notch extracellular domain, EGF epidermal growth factor, LNRs Lin12-Notch repeats, TMD transmembrane domain, NICD Notch intracellular domain, ANK ankyrin repeat, NLS nuclear localization sequences, TAD transcription activation domain, PEST proline/glutamic acid/serine/threonine, CSL CBF1/suppressor of hairless/Lag1, ADAM a disintegrin and metalloprotease, ER endoplasmic reticulum, Co-R corepressor, CSL CBF1/suppressor of hairless/Lag1, Co-A coactivator, MAML mastermind-like

Fig. 2

Involvement of Notch signaling in the regulation of diverse cancers. Notch signaling plays a role in the regulation of various cancers, encompassing digestive system tumors, respiratory system tumors, hematological malignancies, urinary system tumors, reproductive system tumors, nervous system neoplasms, and tumors in other systems. (Figure created using BioRender.com)

Fig. 3

Notch signaling pathway in epithelial-mesenchymal transition (EMT). EMT is a complex process wherein epithelial cells undergo a transition, losing their inherent characteristics and adopting a mesenchymal phenotype. Notch signaling plays a crucial role in regulating EMT, representing a significant mechanism for tumor cells to acquire malignant properties. (Figure created using BioRender.com). ADAM a disintegrin and metalloprotease, N1ICD Notch1 intracellular domain, ZEB1 zinc finger E-box-binding homeobox 1, MCAM melanoma cell adhesion molecule, Co-A coactivator, MAML mastermind-like, CSL CBF1/suppressor of hairless/Lag1

Fig. 4

Notch signaling pathway in tumor angiogenesis. Abnormal angiogenesis, a distinctive feature of the tumor microenvironment, provides essential nutrients for tumor growth and facilitates the entry of malignant cells into circulation, leading to distant metastases. The Notch signaling cascade plays a crucial role in mediating tumor angiogenesis. (Figure created using BioRender.com). VEGFR vascular endothelial growth factor receptor, VEGF vascular endothelial growth factor, MAPK mitogen-activated protein kinase, DLL4 delta-like ligand 4, ADAM a disintegrin and metalloprotease, VEGFA vascular endothelial growth factor A, JAG1 Jagged1, NRP1 neuropilin 1, NRARP Notch-regulated ankyrin repeat protein, FMOD fibromodulin

Fig. 5

Notch signaling pathway in cancer stem-like cell (CSLC) properties. CSLC, a subset of tumor cells with notable self-renewal potential and multidirectional differentiation ability, are regulated by the abnormal activation of the Notch signaling pathway. (Figure created using BioRender.com). iNOS inducible nitric oxide synthase, TACE TNF-alpha converting enzyme, ADAM a disintegrin and metalloprotease, HCC hepatocellular carcinoma, CAFs cancer-associated fibroblasts, LSD1 lysine-specific histone demethylase 1A, CRC colorectal cancer, JAG2 Jagged2, SDF-1 stromal cell-derived factor-1, CXCR4 CXC chemokine receptor 4, RCC renal cell carcinoma, CSC cancer stem cell

Fig. 6

Notch signaling pathway in cancer metabolic reprogramming. Notch signaling plays a crucial role in the metabolic reprogramming of cancer cells, particularly during the glycolytic switch. The Notch pathway is active during this transition in cancer cells, with several genes directly regulated as transcriptional targets. This regulation mediates the shift in cellular metabolism towards the Warburg effect. (Figure created using BioRender.com). CLL chronic lymphocytic leukemia, PTEN phosphatase and tensin homolog, T-ALL T cell acute lymphoblastic leukemia, PI3K/AKT phosphoinositide 3-kinase/protein kinase B, HIF1α hypoxia-inducible factor 1α, Co-A coactivator, MAML mastermind-like, CSL CBF1/suppressor of hairless/Lag1, GLUT glucose transporters, MCT monocarboxylate transporter, ATP adenosine triphosphate, NADH nicotinamide adenine dinucleotide hydride, NAD nicotinamide adenine dinucleotide, TCA tricarboxylic acid, α-KG alpha-ketoglutarate

Fig. 7

Notch signaling pathway in tumor microenvironment (TME). The Notch signaling pathway actively participates in the components of the TME, regulating TME through both paracrine and autocrine signals. (Figure created using BioRender.com). TGF-β2 transforming growth factor-beta2, TGF- βR1 transforming growth factor-beta receptor 1, CRC colorectal cancer, DLL1 delta-like ligand 1, ADAM a disintegrin and metalloprotease, HIF hypoxia-inducible factor, PI3K phosphoinositide 3-kinase, WISP Wnt-induced signaling protein 1, CAFs cancer-associated fibroblasts, HCC hepatocellular carcinoma, PINK1 PTEN-induced putative kinase 1, ROS reactive oxygen species

Fig. 8

Notch signaling pathway in chemoresistance. The aberrant expression and overactivation of Notch pathway components play crucial roles in contributing to chemoresistance. (Figure created with BioRender.com). PDAC pancreatic ductal adenocarcinoma, N1DARP Notch1 degradation-associated regulatory polypeptide, N1ICD Notch1 intracellular domain, CHEMO chemotherapy, SCLC small cell lung cancer, AP-1 activator protein-1, LUAD lung adenocarcinoma, MVP major vault protein, AKT protein kinase B, TNBC triple-negative breast cancer, ADAM a disintegrin and metalloprotease, JAG1-ICD Jagged1 intracellular domain, CRC colorectal cancer

Fig. 9

Notch signaling pathway in tumor suppression. Earlier studies provided evidence supporting Notch-mediated tumor suppression in various malignancies, including SCC, cervical cancer, and SCLC. (Figure created using BioRender.com). PDAC pancreatic ductal adenocarcinoma, MmuPV1 Mus musculus papillomavirus 1, HPV8 human papillomavirus, Co-A coactivator, MAML mastermind-like, CSL CBF1/suppressor of hairless/Lag1, hASH1 human achaete-scute homolog-1, SST somatostatin, SSTR somatostatin receptor, SCC squamous cell carcinoma, SCLC small cell lung cancer

Fig. 10

Therapeutic strategies targeting Notch signaling in human malignancies. Various pharmacological agents aimed at the Notch pathway have been developed, including γ-secretase inhibitors (GSIs), ADAM inhibitors, antibodies against Notch receptors or ligands, inhibitors targeting the Notch transcription complex, and γ-secretase modulators (GSMs). (Figure created with BioRender.com). DLL3 delta-like ligand 3, DLL4 delta-like ligand 4, ADAM a disintegrin and metalloprotease, NECD Notch extracellular domain, NICD Notch intracellular domain, Co-A coactivator, MAML mastermind-like, CSL CBF1/suppressor of hairless/Lag1