Oncogenic Notch Triggers Neoplastic Tumorigenesis in a Transition-Zone-like Tissue Microenvironment

Yang, Sheng-An; Portilla, Juan-Martin; Mihailovic, Sonja; Huang, Yi-Chun; Deng, Wu-Min

doi:10.1016/j.devcel.2019.03.015

Cited by 33 publications

(42 citation statements)

References 74 publications

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“…The Notch signaling pathway is well known for its complexity. Its role in cancer has been extensively studied in the context of oncogenic Notch mutations (28,29). A previous study established a role for Notch in inhibiting osteoblast differentiation, and showed that its activation in committed osteosarcoma cells induces a highly tumorigenic phenotype (13).…”

Section: Discussionmentioning

confidence: 99%

The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling

Xia

Gao

et al. 2019

Molecular Cancer Research

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Despite significant advancements in the diagnosis and treatment of osteosarcoma, the molecular mechanisms underpinning disease progression remain unclear. This work presents strong clinical and experimental evidence demonstrating that Notch signaling contributes to osteosarcoma progression. First, using a cohort of 12 patients, Notch genes were upregulated in tumors compared with adjacent normal tissue, and high tumor expression of Notch1 intercellular domain (NICD1) and the Notch target gene Hes1 correlated with poor chemotherapy response. Data mining of publicly available datasets confirmed that expression of Notch pathway genes is related to poor prognosis in osteosarcoma. On the basis of in vitro analysis, Notch signaling promoted osteosarcoma proliferation, enhanced chemoresistance, facilitated both migration and invasion, and upregulated stem cell-like characteristics. Xenograft models demonstrated that Notch signaling promotes primary tumor growth and pulmonary metastasis, and Notch inhibition is effective in reducing tumor size and preventing metastasis. Mechanistically, activated Notch signaling induces the expression of ephrinB1 and enhances the tumor-promoting ephrin reverse signaling. Overall, these findings provide functional evidence for Notch pathway genes as candidate biomarkers to predict prognosis in patients with osteosarcoma, and suggest a mechanistic rationale for the use of Notch inhibitors to treat osteosarcoma. Implications:The study provides preclinical evidence for Notch pathway as a molecular marker to predict osteosarcoma prognosis and as a therapeutic target against osteosarcoma. In addition, we identified a novel mechanism that ephrin reverse signaling acts as a key mediator of Notch pathway.

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Section: Discussionmentioning

confidence: 99%

The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling

Xia

Gao

et al. 2019

Molecular Cancer Research

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“…(6) Jun N-terminal kinase signalling can be important in tumourigenesis at transition zones -where different epithelial cell populations meet, which are often hotspots for tumourigenesis (reviewed in Tamori and Deng, 2017). One such zone occurs in the Drosophila larvae at a site where polyploid salivary gland cells meet the diploid imaginal ring cells, where tumourigenesis occurs after transient whole animal N ACT expression due to upregulation of TNF-JNK and Jak-STAT signalling (Yang et al, 2019). (7) Overexpression of Canoe (Cno, an adherens junction scaffold protein) in the patched (ptc) expression domain in wing imaginal discs conversely promotes both overproliferation and ectopic cell death, as well as cell migration/invasion .…”

Section: Pro-tumourigenic Jnk Signallingmentioning

confidence: 99%

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

Marca

Richardson

2020

Front. Cell Dev. Biol.

108

106

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“…There are now many animal models for studying cancer, each with advantages and disadvantages (see Table 4). 215‐227 Despite caveats, model organisms (and, in many cases, the simple ones) 222,228,229 have been instrumental in the discovery of fundamental biological mechanisms relating to development, differentiation, cell growth, and cell death—all processes highly relevant to the biology of human cancers. Models in lower eukaryotes (flies, frogs, worms, and fish) are far less expensive to maintain than mammalian models (eg, mouse), their development time is relatively short, and their genomes are far simpler.…”

Section: Cancer Modelingmentioning

confidence: 99%

Blueprint for cancer research: Critical gaps and opportunities

Elmore

Greer

Daniels

et al. 2020

CA A Cancer J Clinicians

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We are experiencing a revolution in cancer. Advances in screening, targeted and immune therapies, big data, computational methodologies, and significant new knowledge of cancer biology are transforming the ways in which we prevent, detect, diagnose, treat, and survive cancer. These advances are enabling durable progress in the goal to achieve personalized cancer care. Despite these gains, more work is needed to develop better tools and strategies to limit cancer as a major health concern. One persistent gap is the inconsistent coordination among researchers and caregivers to implement evidence‐based programs that rely on a fuller understanding of the molecular, cellular, and systems biology mechanisms underpinning different types of cancer. Here, the authors integrate conversations with over 90 leading cancer experts to highlight current challenges, encourage a robust and diverse national research portfolio, and capture timely opportunities to advance evidence‐based approaches for all patients with cancer and for all communities.

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Oncogenic Notch Triggers Neoplastic Tumorigenesis in a Transition-Zone-like Tissue Microenvironment

Cited by 33 publications

References 74 publications

The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling

The Notch Pathway Promotes Osteosarcoma Progression through Activation of Ephrin Reverse Signaling

Two-Faced: Roles of JNK Signalling During Tumourigenesis in the Drosophila Model

Blueprint for cancer research: Critical gaps and opportunities

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