Roles of Notch Signaling in the Tumor Microenvironment

D’Assoro, Antonino B.; Leon‐Ferre, Roberto A.; Braune, Eike-Benjamin; Lendahl, Urban

doi:10.3390/ijms23116241

Cited by 40 publications

(32 citation statements)

References 151 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Final Notch signaling response is a product of integration of both cis and trans cellular signaling and of PDA (45,46). Notch signaling has also been shown to regulate fibroblast phenotype and function in the tumor microenvironment and other inflammatory contexts (47,48). In PDA, cancer-associated fibroblasts can be parsed into multiple coexisting subtypes regulating the tumor microenvironment and immune response (28,(49)(50)(51)(52)(53)(54)(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer

Yan

Steele

Kemp

et al. 2023

Preprint

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, express high levels of Notch receptors with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators including arginase 1 (Arg1) suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Combination of Notch inhibition with PD-1 blockade resulted in increased cytotoxic T cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in PDA patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer

Yan

Steele

Kemp

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In Notch cancer biology, cell context is a major determinant of the striking observation that Notch can be either tumor suppressive or oncogenic in different malignancies (reviewed in (2,(111)(112)(113).…”

Section: Discussionmentioning

confidence: 99%

The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner

DeCotiis-Mauro

Han

Mello

et al. 2022

Preprint

View full text Add to dashboard Cite

The cellular Notch signal transduction pathway is intimately associated with infections by Kaposi’s sarcoma-associated herpesvirus (KSHV) and other gamma-herpesviruses. RBP-Jk, the cellular DNA binding component of the canonical Notch pathway, is the key Notch downstream effector protein in virus-infected and uninfected animal cells. Reactivation of KSHV from latency requires the viral lytic switch protein, Rta, to form complexes with RBP-Jk on numerous sites within the viral DNA. Constitutive Notch activity is essential for KSHV pathophysiology in models of Kaposi’s sarcoma (KS) and Primary Effusion Lymphoma (PEL), and we demonstrate that Notch1 is also constitutively active in infected Vero cells. Although the KSHV genome contains >100 RBP-Jk DNA motifs, we show that none of the four isoforms of activated Notch can productively reactivate the virus from latency in a highly quantitative trans-complementing reporter virus system. Nevertheless, Notch contributed positively to reactivation because broad inhibition of Notch1-4 with gamma secretase inhibitor (GSI) or expression of dominant negative mastermind-like1 (dnMAML1) coactivators severely reduced production of infectious KSHV from Vero cells. In infected PEL cells, we show that reduction of vDNA synthesis by GSI is associated with gene specific reduction of viral transcription. Specific inhibition of Notch1 by siRNA partially reduces production of infectious KSHV, and ectopic activated Notch (NICD1) enhances virus production induced by Valproic Acid (VPA) treatment. We conclude that constitutive Notch activity is required for robust production of infectious KSHV, and our results implicate activated Notch1 as a pro-viral member of a MAML1/RBP-Jk complex during viral reactivation.ImportanceKaposi’s sarcoma-associated herpesvirus (KSHV) manipulates the host cell oncogenic Notch signaling pathway for viral reactivation from latency and cell pathogenesis. KSHV reactivation requires that the viral protein Rta functionally interacts with RBP-Jk, the DNA binding component of the Notch pathway, and with promoter DNA to drive transcription of productive cycle genes. We show that the Notch pathway is constitutively active during KSHV reactivation and is essential for robust production of infectious virus progeny. Inhibiting Notch during reactivation reduces expression of specific viral genes yet does not affect growth of the host cells. Although Notch cannot reactivate KSHV alone, the requisite expression of Rta reveals a previously unappreciated role for Notch in reactivation. We propose that activated Notch cooperates with Rta in a promoter-specific manner that is partially programmed by Rta’s ability to redistribute RBP-Jk DNA binding to the virus during reactivation.

show abstract

“…Thereafter, it was demonstrated that Notch signaling pathway components are fundamental and basically highly conserved in virtually all multicellular organisms ( 43 ). In humans, Notch activation has been detected in various lineages from embryonic stem cells to adult cells during development ( 44 , 45 ).…”

Section: History and Physiological Roles Of Notchmentioning

confidence: 99%

Role of Notch2 pathway in mature B cell malignancies

Mesini

Fiorcari²,

Atene³

et al. 2023

Front. Oncol.

View full text Add to dashboard Cite

In recent decades, the Notch pathway has been characterized as a key regulatory signaling of cell-fate decisions evolutionarily conserved in many organisms and different tissues during lifespan. At the same time, many studies suggest a link between alterations of this signaling and tumor genesis or progression. In lymphopoiesis, the Notch pathway plays a fundamental role in the correct differentiation of T and B cells, but its deregulated activity leads to leukemic onset and evolution. Notch and its ligands Delta/Jagged exhibit a pivotal role in the crosstalk between leukemic cells and their environment. This review is focused in particular on Notch2 receptor activity. Members of Notch2 pathway have been reported to be mutated in Chronic Lymphocytic Leukemia (CLL), Splenic Marginal Zone Lymphoma (SMZL) and Nodal Marginal Zone Lymphoma (NMZL). CLL is a B cell malignancy in which leukemic clones establish supportive crosstalk with non-malignant cells of the tumor microenvironment to grow, survive, and resist even the new generation of drugs. SMZL and NMZL are indolent B cell neoplasms distinguished by a distinct pattern of dissemination. In SMZL leukemic cells affect mainly the spleen, bone marrow, and peripheral blood, while NMZL has a leading nodal distribution. Since Notch2 is involved in the commitment of leukemic cells to the marginal zone as a major regulator of B cell physiological differentiation, it is predominantly affected by the molecular lesions found in both SMZL and NMZL. In light of these findings, a better understanding of the Notch receptor family pathogenic role, in particular Notch2, is desirable because it is still incomplete, not only in the physiological development of B lymphocytes but also in leukemia progression and resistance. Several therapeutic strategies capable of interfering with Notch signaling, such as monoclonal antibodies, enzyme or complex inhibitors, are being analyzed. To avoid the unwanted multiple “on target” toxicity encountered during the systemic inhibition of Notch signaling, the study of an appropriate pharmaceutical formulation is a pressing need. This is why, to date, there are still no Notch-targeted therapies approved. An accurate analysis of the Notch pathway could be useful to drive the discovery of new therapeutic targets and the development of more effective therapies.

show abstract

Roles of Notch Signaling in the Tumor Microenvironment

Cited by 40 publications

References 151 publications

Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer

Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer

The cellular Notch1 Protein Promotes KSHV reactivation in an Rta-dependent manner

Role of Notch2 pathway in mature B cell malignancies

Contact Info

Product

Resources

About