bims-lymeca 2022-06-19 papers

J Biol Chem. 2022 Jun 09. pii: S0021-9258(22)00559-2. [Epub ahead of print] 102118

Regulation of the lysosome by sphingolipids: potential role in aging.

Haiqing Tang, Xiaokun Huang, Shanshan Pang.

Sphingolipids are a class of bioactive complex lipids that have been closely associated with aging and aging-related diseases. However, the mechanism through which sphingolipids control aging has long been a mystery. Emerging studies reveal that sphingolipids exert tight control over lysosomal homeostasis and function, as evidenced by sphingolipid-related diseases, including but not limited to lysosomal storage disorders. These diseases are defined by primary lysosomal defects and a few secondary defects such as mitochondrial dysfunction. Intriguingly, recent research indicates that the majority of these defects are also associated with aging, implying that sphingolipid-related diseases and aging may share common mechanisms. We propose that the lysosome is a pivotal hub for sphingolipid-mediated aging regulation. This review discusses the critical roles of sphingolipid metabolism in regulating various lysosomal functions, with an emphasis on how such regulation may contribute to aging and aging-related diseases.

Keywords: aging; lifespan; lysosomal calcium; lysosomal cell death; lysosome; lysosome-mitochondria communication; mTOR; sphingolipid

DOI: https://doi.org/10.1016/j.jbc.2022.102118

Cell Calcium. 2022 Jun 06. pii: S0143-4160(22)00084-7. [Epub ahead of print]105 102610

T-type channels in cancer cells: Driving in reverse.

Lía Alza, Anna Visa, Judit Herreros, Carles Cantí.

In the strongly polarized membranes of excitable cells, activation of T-type Ca2+ channels (TTCCs) by weak depolarizing stimuli allows the influx of Ca2+ which further amplifies membrane depolarization, thus "recruiting" higher threshold voltage-gated channels to promote action potential firing. Nonetheless, TTCCs perform other functions in the plasma membrane of both excitable and non-excitable cells, in which they regulate a number of biochemical pathways relevant for cell cycle and cell fate. Furthermore, data obtained in the last 20 years have shown the involvement of TTCCs in tumor biology, designating them as promising chemotherapeutic targets. However, their activity in the steadily-depolarized membranes of cancer cells, in which most voltage-gated channels are in the inactivated (nonconducting) state, is counter-intuitive. Here we discuss that in cancer cells weak hyperpolarizing stimuli increase the fraction of open TTCCs which, in association with Ca2+-dependent K+ channels, may critically boost membrane hyperpolarization and driving force for Ca2+ entry through different voltage-independent Ca2+ channels. Available evidence also shows that TTCCs participate in positive feedback circuits with signaling effectors, which may warrant a switch-like activation of pro-proliferative and pro-survival pathways in spite of their low availability. Unravelling TTCC modus operandi in the context of non-excitable membranes may facilitate the development of novel anticancer approaches.

Keywords: Calcium signaling pathways; Calcium-activated potassium channels; Cancer cells; Feedback loops; Membrane potential; Proliferation; Survival; T-type calcium channels

DOI: https://doi.org/10.1016/j.ceca.2022.102610

STAR Protoc. 2022 Jun 17. 3(2): 101438

Tracking and characterization of partial and full epithelial-mesenchymal transition cells in a mouse model of metastatic breast cancer.

Fabiana Lüönd, Natascha Santacroce, Christian Beisel, Laurent Guérard, Thomas R Bürglin, Gerhard Christofori, Nami Sugiyama.

The various stages of epithelial-mesenchymal transition (EMT) generate phenotypically heterogeneous populations of cells. Here, we detail a dual recombinase lineage tracing system using a transgenic mouse model of metastatic breast cancer to trace and characterize breast cancer cells at different EMT stages. We describe analytical steps to label cancer cells at an early partial or a late full EMT state, followed by tracking their behavior in tumor slice cultures. We then characterize their transcriptome by five-cell RNA sequencing. For complete details on the use and execution of this protocol, please refer to Luond et al. (2021).

Keywords: Cancer; Cell Biology; Cell Differentiation; Flow Cytometry/Mass Cytometry; Microscopy; Molecular Biology; RNAseq; Single Cell

DOI: https://doi.org/10.1016/j.xpro.2022.101438

Cell Rep. 2022 Jun 14. pii: S2211-1247(22)00725-2. [Epub ahead of print]39(11): 110943

Vps33B controls Treg cell suppressive function through inhibiting lysosomal nutrient sensing complex-mediated mTORC1 activation.

The suppressive function of regulatory T (Treg) cells is tightly controlled by nutrient-fueled mechanistic target of rapamycin complex 1 (mTORC1) activation, yet its dynamics and negative regulation remain unclear. Here we show that Treg-specific depletion of vacuolar protein sorting 33B (Vps33B) in mice results in defective Treg cell suppressive function and acquisition of effector phenotype, which in turn leads to disturbed T cell homeostasis and boosted antitumor immunity. Mechanistically, Vps33B binds with lysosomal nutrient-sensing complex (LYNUS) and promotes late endosome and lysosome fusion and clearance of the LYNUS-containing late endosome/lysosome, and therefore suppresses mTORC1 activation. Vps33B deficiency in Treg cells results in disordered endosome lysosome fusion, which leads to accumulation of LYNUS that causes elevated mTORC1 activation and hyper-glycolytic metabolism. Taken together, our study reveals that Vps33B maintains Treg cell suppressive function through sustaining endolysosomal homeostasis and therefore restricting amino acid-licensed mTORC1 activation and metabolism.

Keywords: CP: Immunology; CP: Metabolism; Foxp3; Treg; Vps33B; endolysosomal system; mTORC1

DOI: https://doi.org/10.1016/j.celrep.2022.110943

Mol Metab. 2022 Jun 14. pii: S2212-8778(22)00098-9. [Epub ahead of print] 101529

New dawn for cancer cell death: emerging role of lipid metabolism.

Chanjuan Zhang, Neng Zhu, Hongfang Li, Yongzhen Gong, Jia Gu, Yaning Shi, Duanfang Liao, Wei Wang, Aiguo Dai, Li Qin.

BACKGROUND: Resistance to cell death, a protective mechanism for removing damaged cells, is a "Hallmark of Cancer" that is essential for cancer progression. Increasing attention to cancer lipid metabolism has revealed a number of pathways that induce cancer cell death.
SCOPE OF REVIEW: We summarize emerging concepts regarding lipid metabolic reprogramming in cancer that is mainly involved in lipid uptake and trafficking, de novo synthesis and esterification, fatty acid synthesis and oxidation, lipogenesis, and lipolysis. During carcinogenesis and progression, continuous metabolic adaptations are co-opted by cancer cells, to maximize their fitness to the ever-changing environmental. Lipid metabolism and the epigenetic modifying enzymes interact in a bidirectional manner which involves regulating cancer cell death. Moreover, lipids in the tumor microenvironment play unique roles beyond metabolic requirements that promote cancer progression. Finally, we posit potential therapeutic strategies targeting lipid metabolism to improve treatment efficacy and survival of cancer patient.
MAJOR CONCLUSIONS: The profound comprehension of past findings, current trends, and future research directions on resistance to cancer cell death will facilitate the development of novel therapeutic strategies targeting the lipid metabolism.

Keywords: Lipid metabolism; cancer; cell death; therapeutic strategy

DOI: https://doi.org/10.1016/j.molmet.2022.101529