WITHDRAWN: Oncogenic KRAS G12D extrinsically induces an immunosuppressive microenvironment in lung adenocarcinoma.

This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.

Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.

Sirtuin 5 levels are limiting in preserving cardiac function and suppressing fibrosis in response to pressure overload.

Heart failure (HF) is the inability of the heart to pump blood sufficiently to meet the metabolic demands of the body. HF with reduced systolic function is characterized by cardiac hypertrophy, ventricular fibrosis and remodeling, and decreased cardiac contractility, leading to cardiac functional impairment and death. Transverse aortic constriction (TAC) is a well-established model for inducing hypertrophy and HF in rodents. Mice globally deficient in sirtuin 5 (SIRT5), a NAD+-dependent deacylase, are hypersensitive to cardiac stress and display increased mortality after TAC. Prior studies assessing SIRT5 functions in the heart have all employed loss-of-function approaches. In this study, we generated SIRT5 overexpressing (SIRT5OE) mice, and evaluated their response to chronic pressure overload using TAC. Compared to littermate controls, SIRT5OE mice were protected against adverse functional consequences of TAC, left ventricular dilation and impaired ejection fraction. Transcriptomic analysis revealed that SIRT5 suppresses key HF sequelae, including the metabolic switch from fatty acid oxidation to glycolysis, immune activation, and fibrotic signaling pathways. We conclude that SIRT5 is a limiting factor in the preservation of cardiac function in response to experimental pressure overload.