The Role Of Stromal Per2 In Regulation Of Tumorigenesis.

Abstract The tumor microenvironment (TME) comprised of multiple proteins, extracellular matrix(ECM) and various cell types that together promote tumor initiation, progression andhomeostasis in a cell-cell communication manner. In this study, we set to understand howthe stromal circadian clock supports the cancer cells, specifically the contribution of thecore clock gene Per2 to tumor initiation and progression. The circadian clock is anendogenous, evolutionally conserved and ubiquitously expressed pacemaker, consisting ofcell autonomous clocks and a central pacemaker located in the hypothalamussuperchiasmatic nucleus (SCN). Together these clocks synchronize numerous biologicalprocesses between the organism and its environment. Amongst these processes are DNAdamage repair, metabolism, and cell cycle. Several studies showed that disruption ofcircadian rhythms has been associated with various forms of cancer in humans and mice.While Per2 was previously suggested to be a tumor suppressor, in this study we found thatthe core clock gene Per2 in the TME is essential for tumor initiation and metastaticcolonization. Another core gene, Per1, is dispensable. We further showed that lossof Per2 in the TME leads to transcriptional rewiring at early stages of metastasesformation, and suppresses subsequent metastatic tumor progression. Thus, our resultsunravel an unexpected protumorigenic role for the core clock gene Per2 in the TME. Thesefindings may imply a non-circadian role for Per2, differentiating it from Per1 withpotential implications for therapeutic dosing strategies and treatment regimens. Citation Format: Shimrit Mayer, Lee Shaashua, Chen Lior, Hagar Lavon, Alexander Novoselsky, Ruth Scherz-Shouval. The role of stromal Per2 in regulation of tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB244.