BBB seminar: Rajan Gogna
Tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells
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Rajan Gogna
Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark
Cell competition and fitness comparison between cancer and the microenvironment cells determine oncogenic fate. Microenvironments that acquire reduced fitness promote cancer growth and metastasis. Expression of Flower Win in cancer and Flower Lose in the microenvironment is a general feature of solid tumors, and is a prerequisite for cancer cells to gain competitive advantage. However, it is not known whether the expression of Flower Lose and thus reduced microenvironment fitness is a pre-existing condition or is a cancer-induced phenomenon. Here we show that reduced microenvironment fitness is a cancer-induced effect. Cancer cells actively reduce microenvironment fitness by exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma. Upon reaching the tumor microenvironment cells, Tu-Stroma establishes a triplex structure, specifically at Exon3 of Flower gene. The triplex structure alters Exon3 DNA-methylation and initiates a cascade of epigenetic changes resulting in Exon3 exclusion and generation of Flower Lose isoforms. Here we discover that cancer cells are programmed to win competitive interactions with help of Tu-Stroma which non-autonomously controls splicing of Flower gene in the tumor microenvironment cells and forces them to acquire reduced-fitness status. Finally, Tu-Stroma expression in the tumor microenvironment of high-grade serous ovarian carcinoma prognosticates patient survival and controls the tumor growth rate in patients. The conserved pathway of Flower-based fitness comparison is a complex system of cell selection in humans with potential to impact cancer therapy and prognosis by targeting tumor microenvironment.
Chairperson: Frits Alan Thorsen, Department of Biomedicine
