Abstract 4636: Oncogenic Notch triggers neoplastic-tumorigenesis in a transition-zone like tissue microenvironment

Abstract

Abstract The “seed and soil” hypothesis proposed by Stephen Paget (1889) highlights the importance of tissue microenvironment for secondary tumor formation. The microenvironment that promotes primary tumor origination, however, remains largely unclear. Transition zones, where two types of epithelial tissue meet, have been characterized as high-risk sites for tumorigenesis. Here we show that the Drosophila salivary gland (SG) imaginal ring (ImR) can be used as a model to study tumorigenesis in transition zones. We found that constitutive activation of Notch signaling during the third larval instar drives overproliferation and tumor formation in the SG ImR. Interestingly, tumorigenesis always occurs at the posterior end of the ImR, which is a transitional area between the polyploid giant cells and diploid ImR cells. These Notch-induced tumors display disrupted epithelial organization, grow continuously and can metastasize once transplanted into the abdomen of adult flies, suggesting that they have the characteristics of malignant neoplasms. Further analyses revealed that the SG ImR transition zone possesses endogenously high levels of Janus kinase/signal transducers and activators of transcription (JAK-STAT) and c-Jun amino-terminal kinases (JNK), both of which are necessary for tumor growth. In this region, JNK signaling induces the expression of matrix metalloproteinase 1 (MMP1), which is also required for tumor formation in this model system. Furthermore, we found that ectopic MMP1 expression can transform the anterior end of the SG ImR, which is normally refractory to oncogenic Notch-induced tumorigenesis, into a tumor hotspot. Together, these studies reveal that local endogenous activation of JNK and JAK-STAT signaling creates a niche-like tissue microenvironment that is susceptible to oncogene-induced neoplastic tumor formation. Citation Format: Wu-Min Deng, Sheng-An Yang. Oncogenic Notch triggers neoplastic-tumorigenesis in a transition-zone like tissue microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4636.