bims-stacyt 2024-12-15 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–12–15
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.
Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.
Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment.
Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis.
Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.
The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration by promoting metabolic reprogramming.
Iron regulates MT1-MMP-mediated proMMP-2 activation and cancer cell invasion.
Polysulfide and persulfide-mediated activation of the PERK-eIF2α-ATF4 pathway increases Sestrin2 expression and reduces methylglyoxal toxicity.
Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1.

Brain Behav Immun. 2024 Dec 11. pii: S0889-1591(24)00739-6. [Epub ahead of print]

GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.

Germana Cocozza, Ludovica Maria Busdraghi, Giuseppina Chece, Antonio Menini, Marco Ceccanti, Laura Libonati, Chiara Cambieri, Francesco Fiorentino, Dante Rotili, Ferdinando Scavizzi, Marcello Raspa, Eleonora Aronica, Maurizio Inghilleri, Stefano Garofalo, Cristina Limatola.

  Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.

Keywords:  Adipose tissue; Feeding behaviour; GDF15; GFRAL; Microglia; Neurodegenerative disease

DOI:  https://doi.org/10.1016/j.bbi.2024.12.010
Nature. 2024 Dec 11.

Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours.

Ignacio Melero, Maria de Miguel Luken, Guillermo de Velasco, Elena Garralda, Juan Martín-Liberal, Markus Joerger, Guzman Alonso, Maria-Elisabeth Goebeler, Martin Schuler, David König, Reinhard Dummer, Maria Reig, Maria-Esperanza Rodriguez Ruiz, Emiliano Calvo, Jorge Esteban-Villarrubia, Arjun Oberoi, Paula Sabat, Juan José Soto-Castillo, Kira-Lee Koster, Omar Saavedra, Cyrus Sayehli, Tanja Gromke, Heinz Läubli, Egle Ramelyte, Marta Fortuny, Ana Landa-Magdalena, Irene Moreno, Javier Torres-Jiménez, Alberto Hernando-Calvo, Dagmar Hess, Fabricio Racca, Heike Richly, Andreas M Schmitt, Corinne Eggenschwiler, Marco Sanduzzi-Zamparelli, Anna Vilalta-Lacarra, Jörg Trojan, Christine Koch, Peter R Galle, Friedrich Foerster, Zlatko Trajanoski, Hubert Hackl, Falk Gogolla, Florestan J Koll, Peter Wild, Felix Kyoung Hwan Chun, Henning Reis, Peter Lloyd, Matthias Machacek, Thomas F Gajewski, Wolf H Fridman, Alexander M M Eggermont, Ralf Bargou, Sandra Schöniger, Josef Rüschoff, Anastasiia Tereshchenko, Carina Zink, Antonio da Silva, Felix S Lichtenegger, Julia Akdemir, Manfred Rüdiger, Phil L'Huillier, Aradhana Dutta, Markus Haake, Alexandra Auckenthaler, Ana Gjorgjioska, Bernhard Rössler, Frank Hermann, Mara Liebig, Daniela Reichhardt, Christine Schuberth-Wagner, Jörg Wischhusen, Petra Fettes, Marlene Auer, Kathrin Klar, Eugen Leo.

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment1. Yet, response rates are still limited, and tumour progression commonly occurs2. Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition3. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

DOI: https://doi.org/10.1038/s41586-024-08305-z
Biochim Biophys Acta Rev Cancer. 2024 Dec 11. pii: S0304-419X(24)00175-6. [Epub ahead of print] 189244

Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment.

Helena Branco, Cristina P R Xavier, Chiara Riganti, M Helena Vasconcelos.

  In the past years, increasing attention has been paid to the role of extracellular vesicles (EVs) as mediators of intercellular communication in cancer. These small size particles mediate the intercellular transfer of important bioactive molecules involved in malignant initiation and progression. Hypoxia, or low partial pressure of oxygen, is recognized as a remarkable feature of solid tumors and has been demonstrated to exert a profound impact on tumor prognosis and therapeutic efficacy. Indeed, the high-pitched growth rate and chaotic neovascular architecture that embodies solid tumors results in a profound reduction in oxygen pressure within the tumor microenvironment (TME). In response to oxygen-deprived conditions, tumor cells and their surrounding milieu develop homeostatic adaptation mechanisms that contribute to the establishment of a pro-tumoral phenotype. Latest evidence suggests that the hypoxic microenvironment that surrounds the tumor bulk may be a clincher for the observed elevated levels of circulating EVs in cancer patients. Thus, it is proposed that EVs may play a role in mediating intercellular communication in response to hypoxic conditions. This review focuses on the EVs-mediated crosstalk that is established between tumor cells and their surrounding immune, endothelial, and stromal cell populations, within the hypoxic TME.

Keywords:  Extracellular vesicles; Hypoxia; Intercellular communication; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2024.189244
Heliyon. 2024 Dec 15. 10(23): e39491

Cancer specific up-regulated lactate genes associated with immunotherapy resistance in a pan-cancer analysis.

Shuiting Fu, Jiachen Xu, Chunming Wang, Cheng Zhang, Chengcheng Li, Wenchuan Xie, Guoqiang Wang, Xin Zhu, Yuyan Xu, Yaohong Wen, Jingyuan Pei, Jun Yang, Mingyang Tang, Hongkun Tan, Shangli Cai, Lei Cai, Mingxin Pan.

   Background: Although the lactate pathway has been reported to lead to immune escape through the inhibition of effector T cells, the cancer-intrinsic lactate signature has not been identified, and the immunotherapeutic efficacy and potential mechanism of the lactate signature are still unclear.
Methods: We defined a pan-cancer up-lactate score by comparing malignant tissues and normal tissues in the TCGA cohort. The immunotherapeutic efficacy was evaluated in non-small cell lung cancer (NSCLC), metastatic renal cancer (mRCC), bladder cancer (BLCA) and melanoma cohorts. The cancer cell-intrinsic mechanism to immune checkpoint inhibitors (ICIs) resistance was measured using single cell sequencing (scRNA-seq) data. Pathway activation was evaluated in the TCGA cohort and CPTAC cohort with transcriptomics and proteomics. The co-occurrence of up-lactate signature and mTOR signaling was determined by spatial transcriptomics of the tissue samples. Immunotherapy resistance and pathway regulation were validated in the in-house NSCLC cohort.
Results: Patients with the high up-lactate scores had significantly short overall survival (OS) than those with the low up-lactate scores (p < 0.001) across multiple types of cancers. The up-regulated lactate signature exhibited higher expression in the malignant cells compared with stromal cells and immune cells in multiple scRNA-seq datasets. A high up-lactate score was associated with poor OS in NSCLC, mRCC, BLCA and melanoma patients who received anti-PD(L)1 antibody. The up-lactate score was higher in the responders of cancer cells, but not in immune cells and stromal cells compared with the non-responders (p < 0.05). Moreover, up-lactate score was positively correlated with mTOR signaling across multiple cancers. In patients with NSCLC who received anti-PD-1 antibody, higher up-lactate scores were associated with significantly shorter PFS compared to lower up-lactate scores (p < 0.001). Additionally, the up-lactate score was associated with cold tumor, and was positively correlated with mTOR signaling.
Conclusion: Collectively, we defined a pan-cancer up-lactate signature, which is a feature of malignant cells and is associated with ICIs resistance. This reveals a coherent program with prognostic and predictive value that may be therapeutically targeted.

Keywords:  Cancer intrinsic feature; Immune checkpoint inhibitor; Immunosuppression; Lactate

DOI:  https://doi.org/10.1016/j.heliyon.2024.e39491
bioRxiv. 2024 Nov 26. pii: 2024.09.27.615385. [Epub ahead of print]

Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.

Deena B Snoke, Jos L van der Velden, Emma R Bellafleur, Jacob S Dearborn, Sean M Lenahan, Skyler C J Heininger, Jennifer L Ather, Hailey Sarausky, Daniel Stephenson, Julie A Reisz, Angelo D'Alessandro, Devdoot Majumdar, Thomas P Ahern, Kim L Sandler, Bennett A Landman, Yvonne M W Janssen-Heininger, Matthew E Poynter, David J Seward, Michael J Toth.

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific Kras G12D/+ ( G12D ) mice. G12D mice develop CC over a protracted time course and phenocopy tissue, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. CC in G12D mice is characterized by early loss of adipose tissue, a phenotype confirmed in a large cohort of patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.

DOI: https://doi.org/10.1101/2024.09.27.615385
Discov Immunol. 2024 ;3(1): kyae016

The sedoheptulose kinase CARKL controls T-cell cytokine outputs and migration by promoting metabolic reprogramming.

Michelangelo Certo, Jennifer Niven, Robert Haas, Paula Rudzinska, Joanne Smith, Danilo Cucchi, Jose R Hombrebueno, Claudio Mauro.

   Background: Immunometabolism is a crucial determinant of immune cell function, influencing cellular activation and differentiation through metabolic pathways. The intricate interplay between metabolism and immune responses is highlighted by the distinct metabolic programs utilized by immune cells to support their functions. Of particular interest is the pentose phosphate pathway (PPP), a key metabolic pathway branching out of glycolysis that plays a pivotal role in generating NADPH and pentose sugars crucial for antioxidant defense and biosynthesis. The sedoheptulose kinase Carbohydrate Kinase-like protein (CARKL), an enzyme involved in the PPP, emerges as a critical regulator of cell metabolism and was previously shown to play a role in macrophage function.
Methods: This study delves into the impact of CARKL expression on T-cell functionality, revealing dynamic alterations in response to cellular activation. Notably, CARKL overexpression leads to significant metabolic shifts in T cells, affecting mitochondrial respiration, ATP production, and inflammatory cytokine profiles. Furthermore, CARKL modulation influences T-cell motility by regulating chemokine receptor expression, particularly compromising CXCR3 expression and impairing T-cell migration in response to specific chemokine signals.
Conclusions: These findings underscore the multifaceted role of CARKL as a metabolic regulator shaping T-cell responses. Overall, our data reveal the complex regulatory mechanisms orchestrated by CARKL in T-cell function, with implications for immune regulation. Further exploration of the molecular interactions between CARKL and metabolic reprogramming in T cells could provide valuable insights into immune regulation and potential therapeutic strategies.

Keywords:  CARKL; T cells; immunometabolism; inflammation; pentose phosphate pathway; reprogramming

DOI:  https://doi.org/10.1093/discim/kyae016
Biochem Biophys Res Commun. 2024 Dec 03. pii: S0006-291X(24)01660-7. [Epub ahead of print]742 151124

Iron regulates MT1-MMP-mediated proMMP-2 activation and cancer cell invasion.

Risa Takatsuka, Minoru Terashima, Akihiko Ishimura, Takeshi Suzuki, Takahisa Takino.

  Cellular iron plays a crucial role in many crucial physiological processes. Excessive iron retention due to iron influx and efflux imbalance contributes to cancer development and proliferation, as well as malignant conversion. Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a crucial role in tumor invasion and metastasis, because this enzyme can degrade various extracellular matrix components and cleave membrane tethered proteins on the cell surface. Herein, we demonstrate that cellular iron regulates MT1-MMP-mediated proMMP-2 activation and thereby cancer cell invasion. Iron depletion downregulated MT1-MMP expression in cancer cells, accompanied by inhibition of proMMP-2 activation. Conversely, iron loading stimulated MT1-MMP expression and MT1-MMP-containing extracellular vesicle secretion, thereby promoting proMMP-2 activation, which was inhibited through antioxidant treatment. Iron chelator deferasirox suppressed cancer cell invasion but not fibroblasts. Thus, this study indicated that iron accumulation in cancer may contribute to not only cell proliferation but also invasion by activating the MT1-MMP-MMP-2 axis.

Keywords:  ECM; Invasion; Iron; MT1-MMP; Migration

DOI:  https://doi.org/10.1016/j.bbrc.2024.151124
Redox Biol. 2024 Dec 05. pii: S2213-2317(24)00428-2. [Epub ahead of print]79 103450

Polysulfide and persulfide-mediated activation of the PERK-eIF2α-ATF4 pathway increases Sestrin2 expression and reduces methylglyoxal toxicity.

Shin Koike, Hideo Kimura, Yuki Ogasawara.

  Unfolded protein response (UPR) is activated in cells under endoplasmic reticulum (ER) stress. One sensor protein involved in this response is PERK, which is activated through its redox-dependent oligomerization. Prolonged UPR activation is associated with the development and progression of various diseases, making it essential to understanding the redox regulation of PERK. Sulfane sulfur, such as polysulfides and persulfides, can modify the cysteine residues and regulate the function of various proteins. However, the regulatory mechanism and physiological effects of sulfane sulfur on the PERK-eIF2α-ATF4 pathway remain poorly understood. This study focuses on the persulfidation of PERK to elucidate the effects of polysulfides on the PERK-eIF2α-ATF4 pathway and investigate its cytoprotective mechanism. Here, we demonstrated that polysulfide treatment promoted the oligomerization of PERK and PTP1B in neuronal cells using western blotting under nonreducing conditions. We also observed that l-cysteine, a biological source of sulfane sulfur, promoted the oligomerization of PERK and the knockdown of CBS and 3-MST, two sulfane sulfur-producing enzymes, and reduced PERK oligomerization induced by l-cysteine treatment. Furthermore, the band shift assay and LC-MS/MS studies revealed that polysulfides and persulfides induce PTP1B and PERK persulfidation. Additionally, polysulfides promoted eIF2α phosphorylation and ATF4 accumulation in the nucleus, suggesting that polysulfides activate the PERK-eIF2α-ATF4 pathway in neuronal cells. Moreover, polysulfides protected neuronal cells from methylglyoxal-induced toxicity, and this protective effect was reduced when the expression of Sestrin2, regulated by ATF4 activity, was suppressed. This study identified a novel mechanism for the activation of the PERK-eIF2α-ATF4 pathway through persulfidation by polysulfides and persulfides. Interestingly, activation of this pathway overcame the toxicity of methylglyoxal in dependence on Sestrin2 expression. These findings deepen our understanding of neuronal diseases involving ER stress and UPR disturbance and may inspire new therapeutic strategies.

Keywords:  Methylglyoxal; Persulfide; Polysulfide; Sestrin2; UPR pathway

DOI:  https://doi.org/10.1016/j.redox.2024.103450
Oncogene. 2024 Dec 11.

Senescent lung fibroblasts in idiopathic pulmonary fibrosis facilitate non-small cell lung cancer progression by secreting exosomal MMP1.

Yuqiong Lei, Cheng Zhong, Jingyuan Zhang, Qi Zheng, Yongle Xu, Zhoubin Li, Chenwen Huang, Tao Ren.

Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.

DOI: https://doi.org/10.1038/s41388-024-03236-5