In a study using Drosophila, the research group of Professor Tatsushi Igaki and Assistant Professor Masato Enomoto of the Graduate School of Biostudies, Kyoto University, discovered that benign tumor cells with different gene mutations acquire the ability to infiltrate the basement membrane, and gain metastatic potential when they are adjacent to each other. The researchers were also able to clarify the underlying mechanism for the first time. This is the first example of the mechanism underlying cancer progression related to tumor heterogeneity being clarified. This mechanism is likely a potential new drug target in cancer. The findings were published online in Developmental Cell.
The research group introduced various types of oncogenic mutations into the compound eye tissue of Drosophila. It was clarified that benign tumor cells that activated Ras and those that activated Src3 have infiltrative and metastatic potential when they are adjacent to each other. Expression of Delta ligands in Ras cells and Notch receptors in Src3 cells is elevated, and both interact extracellularly to activate Notch signals in Src3 cells. The Notch signal downregulates expression of E- cadherin, which adheres cells to each other, and Hid protein, which induces cell death, by upregulating the expression of the transcriptional regulator Zfh1 (ZEB1 in humans). It was found that this phenomenon facilitated the infiltration and metastasis of benign tumor cells. Activation of the Notch signal in Src-overexpressing cells results in the upregulation of IL6, which when secreted extracellularly activates the JAK-STAT pathway in Ras-overexpressing tumor cells via the surface receptor of an adjacent Ras-overexpressing cell. The expression of E-cadherin decreases even in Ras-overexpressing tumor cells, which then become cancerous.
Two distinct benign tumors (Ras cells and Src cells) are mutually transformed into malignant tumors via Notch-mediated cell-cell commutation when coexisted in Drosophila epithelial tissue.
Credit: Masato Enomoto and Tatsushi Igaki
Professor Igaki said, "This is the first report on this phenomenon, so I would like to first confirm that the same thing is happening in mouse and human cancer cells. Then, I would like to proceed with research on a new cancer treatment that targets Delta and Notch."
This article has been translated by JST with permission from The Science News Ltd.(https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.