bims-stacyt 2024-08-25 papers

PLoS One. 2024 ;19(8): e0309394

Neutralizing antibody against GDF15 for treatment of cancer-associated cachexia.

Junyi Xiong, Guojin Wu, Jinying Ning, Junlin Yan, Jian Yang, Jinsen Kang.

GDF15 (growth differentiation factor 15), also known as macrophage inhibitory cytokine 1 (MIC-1), is a circulating protein involved in the regulation of energy balance and weight control. Elevated levels of GDF15 have been associated with cachexia and reduced survival rates in cancer patients. Through the activation of the GFRAL (GDNF-family receptor α-like)-RET (Rearranged during Transfection) signaling pathway, GDF15 can induce weight loss, making it a potential target for treating cachexia. Currently, there are no approved antibody drugs specifically targeting GDF15 for cancer cachexia treatment. However, efforts have been made to develop antibody-based therapeutics against this emerging target. In this study, we generated a monoclonal antibody KY-NAb-GDF15 against GDF15 that effectively blocks downstream signaling mediated by GFRAL upon stimulation by GDF15. This antibody demonstrates robust neutralizing activity and exhibits high binding specificity. Importantly, our findings indicate that this antibody holds promise in alleviating cancer-induced cachexia and mitigating chemotherapy-induced weight loss, thereby offering significant therapeutic potential for managing cancer cachexia.

DOI: https://doi.org/10.1371/journal.pone.0309394

Clin Nutr. 2024 Aug 20. pii: S0261-5614(24)00293-0. [Epub ahead of print]43(9): 2236-2237

Reply - Letter to the Editor "Further insights into the association of Growth differentiation factor 15 (GDF15) levels and malnutrition in acutely admitted older adults".

Rikke Lundsgaard Nielsen, Olivia Bornæs, Esben Iversen, Louise Westberg Strejby Christensen, Thomas Kallemose, Baker Jawad, Henrik Højgaard Rasmussen, Tina Munk, Trine Meldgaard Lund, Ove Andersen, Morten Baltzer Houlind, Aino Leegaard Andersen, Juliette Tavenier.

Keywords: Appetite; Chronic inflammation; Emergency care; Malnutrition; Older adults; Physical function

DOI: https://doi.org/10.1016/j.clnu.2024.08.015

Int J Nanomedicine. 2024 ;19 8211-8236

Hypoxia-Driven Changes in Tumor Microenvironment: Insights into Exosome-Mediated Cell Interactions.

Churan Wang, Shun Xu, Xiao Yang.

Hypoxia, as a prominent feature of the tumor microenvironment, has a profound impact on the multicomponent changes within this environment. Under hypoxic conditions, the malignant phenotype of tumor cells, the variety of cell types within the tumor microenvironment, as well as intercellular communication and material exchange, undergo complex alterations. These changes provide significant prospects for exploring the mechanisms of tumor development under different microenvironmental conditions and for devising therapeutic strategies. Exosomes secreted by tumor cells and stromal cells are integral components of the tumor microenvironment, serving as crucial mediators of intercellular communication and material exchange, and have consequently garnered increasing attention from researchers. This review focuses on the mechanisms by which hypoxic conditions promote the release of exosomes by tumor cells and alter their encapsulated contents. It also examines the effects of exosomes derived from tumor cells, immune cells, and other cell types under hypoxic conditions on the tumor microenvironment. Additionally, we summarize current research progress on the potential clinical applications of exosomes under hypoxic conditions and propose future research directions in this field.

Keywords: exosomes; hypoxia; tumor microenvironment; vesicles

DOI: https://doi.org/10.2147/IJN.S479533

Cell Rep. 2024 Aug 18. pii: S2211-1247(24)00982-3. [Epub ahead of print]43(8): 114632

Aerobic glycolysis but not GLS1-dependent glutamine metabolism is critical for anti-tumor immunity and response to checkpoint inhibition.

Patrick M Gubser, Sharanya Wijesinghe, Leonie Heyden, Sarah S Gabriel, David P de Souza, Christoph Hess, Malcolm M McConville, Daniel T Utzschneider, Axel Kallies.

Tumor cells undergo uncontrolled proliferation driven by enhanced anabolic metabolism including glycolysis and glutaminolysis. Targeting these pathways to inhibit cancer growth is a strategy for cancer treatment. Critically, however, tumor-responsive T cells share metabolic features with cancer cells, making them susceptible to these treatments as well. Here, we assess the impact on anti-tumor T cell immunity and T cell exhaustion by genetic ablation of lactate dehydrogenase A (LDHA) and glutaminase1 (GLS1), key enzymes in aerobic glycolysis and glutaminolysis. Loss of LDHA severely impairs expansion of T cells in response to tumors and chronic infection. In contrast, T cells lacking GLS1 can compensate for impaired glutaminolysis by engaging alternative pathways, including upregulation of asparagine synthetase, and thus efficiently respond to tumor challenge and chronic infection as well as immune checkpoint blockade. Targeting GLS1-dependent glutaminolysis, but not aerobic glycolysis, may therefore be a successful strategy in cancer treatment, particularly in combination with immunotherapy.

Keywords: CP: Cancer; CP: Metabolism; GLS1; LDHA; Tpex

DOI: https://doi.org/10.1016/j.celrep.2024.114632

Nat Metab. 2024 Aug 19.

Cancer tissue of origin constrains the growth and metabolism of metastases.

Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize.

DOI: https://doi.org/10.1038/s42255-024-01105-9

J Leukoc Biol. 2024 Aug 23. pii: qiae178. [Epub ahead of print]

Leukemia inhibitory factor drives transcriptional programs that promote lipid accumulation and M2 polarization in macrophages.

Visnu Chaparro, Louis-Philippe Leroux, Aurore Lebourg, Sophie Chagneau, Tyson E Graber, Tommy Alain, Maritza Jaramillo.

Leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, plays a central role in homeostasis and disease. Interestingly, some of the pleiotropic effects of LIF have been attributed to the modulation of macrophage functions although the molecular underpinnings have not been explored at a genome-wide scale. Herein, we investigated LIF-driven transcriptional changes in murine bone marrow-derived macrophages (BMDM) by RNA-seq. In silico analyses revealed a selective and time-dependent remodelling of macrophage gene expression programs associated with lipid metabolism and cell activation. Accordingly, a subset of LIF-upregulated transcripts related to cholesterol metabolism and lipid internalization was validated by RT-qPCR. This was accompanied by a LIF-enhanced capacity for lipid accumulation in macrophages upon incubation with oxidated low-density lipoprotein (Ox-LDL). Mechanistically, LIF triggered the phosphorylation (Y705 and S727) and nuclear translocation of the transcription factor STAT3 in BMDM. Consistent with this, Ingenuity Pathway Analysis (IPA) identified STAT3 as an upstream regulator of a subset of transcripts, including Il4ra, in LIF-treated macrophages. Notably, LIF priming enhanced BMDM responses to IL-4-mediated M2 polarization (i.e., increased arginase activity and accumulation of transcripts encoding for M2 markers). Conversely, LIF stimulation had no significant effect in BMDM responses to M1 polarizing stimuli (IFNγ and LPS). Thus, our study provides insight into the transcriptional landscape of LIF-treated macrophages, shedding light on its role in lipid metabolism and M2 polarization responses. A better understanding of the regulatory mechanisms governing LIF-driven changes might help informing novel therapeutic approaches aiming to reprogram macrophage phenotypes in diseased states (e.g., cancer, atherosclerosis, infection, etc.).

Keywords: IL-4; Leukemia inhibitory factor (LIF); STAT3; cytokine; inflammation; lipids; macrophage; metabolism; polarization

DOI: https://doi.org/10.1093/jleuko/qiae178