Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration.

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction.

Senescent cells accumulate in organisms over time because of tissue damage and impaired immune surveillance and contribute to age-related tissue decline. In agreement, genetic ablation studies reveal that elimination of senescent cells from aged tissues can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs capable of eliminating senescent cells (known as 'senolytics') partially replicate these phenotypes, many have undefined mechanisms of action and all require continuous administration to be effective.

ATG7 is a haploinsufficient repressor of tumor progression and promoter of metastasis.

The role of autophagy in cancer is complex. Both tumor-promoting and tumor-suppressive effects are reported, with tumor type, stage and specific genetic lesions dictating the role. This calls for analysis in models that best recapitulate each tumor type, from initiation to metastatic disease, to specifically understand the contribution of autophagy in each context.

DRAM-4 and DRAM-5 are compensatory regulators of autophagy and cell survival in nutrient-deprived conditions.

Macroautophagy is a membrane-trafficking process that delivers cytoplasmic material to lysosomes for degradation. The process preserves cellular integrity by removing damaged cellular constituents and can promote cell survival by providing substrates for energy production during hiatuses of nutrient availability. The process is also highly responsive to other forms of cellular stress.

Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver.

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction.

MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype.

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this -driven PDAC switch is completely and immediately reversible: deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells.

mTORC1 Activation Requires DRAM-1 by Facilitating Lysosomal Amino Acid Efflux.

Sensing nutrient availability is essential for appropriate cellular growth, and mTORC1 is a major regulator of this process. Mechanisms causing mTORC1 activation are, however, complex and diverse. We report here an additional important step in the activation of mTORC1, which regulates the efflux of amino acids from lysosomes into the cytoplasm.

Mannose impairs tumour growth and enhances chemotherapy.

It is now well established that tumours undergo changes in cellular metabolism. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy.

Autophagy in Neurodegeneration: Can't Digest It, Spit It Out!

The autophagy-lysosome pathway maintains cellular homeostasis and protects against neurodegenerative disorders. Recent findings show that autophagy can be impaired in these diseases, and that the cell activates an alternative Golgi-mediated degradation pathway, leading to expulsion of toxic protein aggregates. Ultimately this process leads to nuclear breakdown and neuronal cell death.