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Background and aims: In stomach, metaplasia can arise from differentiated chief cells that become mitotic via paligenosis, a stepwise program. In paligenosis, mitosis initiation requires reactivation of the cellular energy hub mTORC1 after initial mTORC1 suppression by DNA damage induced transcript 4 (DDIT4 aka REDD1). Here, we use DDIT4-deficient mice and human cells to study how metaplasia increases tumorigenesis risk. Methods: A tissue microarray of human gastric tissue specimens was analyzed by immunohistochemistry for DDIT4. C57BL/6 mice were administered combinations of intraperitoneal injections of high-dose tamoxifen (TAM) to induce spasmolytic polypeptide-expressing metaplasia (SPEM) and rapamycin to block mTORC1 activity, and N-methyl-N-nitrosourea (MNU) in drinking water to induce spontaneous gastric tumors. Stomachs were analyzed for proliferation, DNA damage, and tumor formation. CRISPR/Cas9-generated DDIT4 -/- and control human gastric cells were analyzed for growth in vitro and in xenografts with and without 5-fluorouracil (5-FU) treatment. Results: DDIT4 was expressed in normal gastric chief cells in mice and humans and decreased as chief cells became metaplastic. Paligenotic Ddit4 -/- chief cells maintained constitutively high mTORC1, causing increased mitosis of metaplastic cells despite DNA damage. Lower DDIT4 expression correlated with longer survival of patients with gastric cancer. 5-FU-treated DDIT4 -/- human gastric epithelial cells had significantly increased cells entering mitosis despite DNA damage and increased proliferation in vitro and in xenografts. MNU-treated Ddit4 -/- mice had increased spontaneous tumorigenesis after multiple rounds of paligenosis induced by TAM. Conclusions: During injury-induced metaplastic proliferation, failure of licensing mTORC1 reactivation correlates with increased proliferation of cells harboring DNA damage, as well as increased tumor formation and growth in mice and humans.

Community, As the reality of systemic racism takes front and center across our nation, the Minnesota community mourns the death of George Floyd at the hands of the Minneapolis Police Department. Minnesota Ultimate stands in solidarity with the family, friends, and community of George Floyd, Breonna Taylor, Ahmaud Arbery, and all others grieving due to police violence. We refuse to be silent any longer. Urgent and sustained action is required of all people in order for Black Lives to truly matter.Unfortunately, the ultimate community is not free from contributing to the oppression of Black, Indigenous, and People of Color. We are committed to assessing where our organization falls short while also holding ourselves accountable to allocating resources in a way that begins to address these racial injustices. Minnesota Ultimate