bims-stacyt 2024-04-28 papers

EMBO Rep. 2024 Apr 26.

IL-6 promotes tumor growth through immune evasion but is dispensable for cachexia.

Various cytokines have been implicated in cancer cachexia. One such cytokine is IL-6, deemed as a key cachectic factor in mice inoculated with colon carcinoma 26 (C26) cells, a widely used cancer cachexia model. Here we tested the causal role of IL-6 in cancer cachexia by knocking out the IL-6 gene in C26 cells. We found that the growth of IL-6 KO tumors was dramatically delayed. More strikingly, while IL-6 KO tumors eventually reached the similar size as wild-type tumors, cachexia still took place, despite no elevation in circulating IL-6. In addition, the knockout of leukemia inhibitory factor (LIF), another IL-6 family cytokine proposed as a cachectic factor in the model, also affected tumor growth but not cachexia. We further showed an increase in the infiltration of immune cell population in the IL-6 KO tumors compared with wild-type controls and the defective IL-6 KO tumor growth was rescued in immunodeficient mice while cachexia was not. Thus, IL-6 promotes tumor growth by facilitating immune evasion but is dispensable for cachexia.

Keywords: Cancer Cachexia; Colon Carcinoma 26; IL-6; LIF; Tumor Immune Evasion

DOI: https://doi.org/10.1038/s44319-024-00144-3

Nat Rev Immunol. 2024 Apr 22.

Cancer cell metabolism and antitumour immunity.

Mara De Martino, Jeffrey C Rathmell, Lorenzo Galluzzi, Claire Vanpouille-Box.

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

DOI: https://doi.org/10.1038/s41577-024-01026-4

Aging Cell. 2024 Apr 22. e14111

Downregulation of PLIN2 in human dermal fibroblasts impairs mitochondrial function in an age-dependent fashion and induces cell senescence via GDF15.

Antonio Chiariello, Luca Rossetti, Sabrina Valente, Gianandrea Pasquinelli, Manuela Sollazzo, Luisa Iommarini, Anna Maria Porcelli, Monica Tognocchi, Giuseppe Conte, Aurelia Santoro, Katarzyna M Kwiatkowska, Paolo Garagnani, Stefano Salvioli, Maria Conte.

Perilipin 2 (PLIN2) is a lipid droplet (LD)-coating protein playing important roles in lipid homeostasis and suppression of lipotoxicity in different tissues and cell types. Recently, a role for PLIN2 in supporting mitochondrial function has emerged. PLIN2 dysregulation is involved in many metabolic disorders and age-related diseases. However, the exact consequences of PLIN2 dysregulation are not yet completely understood. In this study, we knocked down (KD) PLIN2 in primary human dermal fibroblasts (hDFs) from young (mean age 29 years) and old (mean age 71 years) healthy donors. We have found that PLIN2 KD caused a decline of mitochondrial function only in hDFs from young donors, while mitochondria of hDFs from old donors (that are already partially impaired) did not significantly worsen upon PLIN2 KD. This mitochondrial impairment is associated with the increased expression of the stress-related mitokine growth differentiation factor 15 (GDF15) and the induction of cell senescence. Interestingly, the simultaneous KD of PLIN2 and GDF15 abrogated the induction of cell senescence, suggesting that the increase in GDF15 is the mediator of this phenomenon. Moreover, GDF15 KD caused a profound alteration of gene expression, as observed by RNA-Seq analysis. After a more stringent analysis, this alteration remained statistically significant only in hDFs from young subjects, further supporting the idea that cells from old and young donors react differently when undergoing manipulation of either PLIN2 or GDF15 genes, with the latter being likely a downstream mediator of the former.

Keywords: GDF15; PLIN2; cell senescence; human aging; lipid metabolism; mitochondrial dysfunction

DOI: https://doi.org/10.1111/acel.14111