bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–04–16
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Body composition and lung cancer-associated cachexia in TRACERx.
  2. The dysregulation of leukemia inhibitory factor and its implications for endometriosis pathophysiology.
  3. AMPK reduces macrophage endotoxin tolerance through inhibition of TGF-β1 production and its signaling pathway.
  4. Growth differentiation factor 15 protects the airway by inhibiting cell pyroptosis in obese asthmatic mice through the phosphoinositide 3-kinase/AKT pathway.
  5. Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations.
  6. Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers.
  1. Nat Med. 2023 Apr 12.
    Body composition and lung cancer-associated cachexia in TRACERx.
    TRACERx Consortium
      Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
    DOI:  https://doi.org/10.1038/s41591-023-02232-8
  2. Front Immunol. 2023 ;14 1089098
    The dysregulation of leukemia inhibitory factor and its implications for endometriosis pathophysiology.
    Katherine B Zutautas, Danielle J Sisnett, Jessica E Miller, Harshavardhan Lingegowda, Timothy Childs, Olga Bougie, Bruce A Lessey, Chandrakant Tayade.
      Endometriosis is an estrogen dominant, chronic inflammatory disease characterized by the growth of endometrial-like tissue outside of the uterus. The most common symptoms experienced by patients include manifestations of chronic pelvic pain- such as pain with urination, menstruation, or defecation, and infertility. Alterations to Leukemia Inhibitory Factor (LIF), a cytokine produced by the luminal and glandular epithelium of the endometrium that is imperative for successful pregnancy, have been postulated to contribute to infertility. Conditions such as recurrent implantation failure, unexplained infertility, and infertility associated diseases such as adenomyosis and endometriosis, have demonstrated reduced LIF production in the endometrium of infertile patients compared to fertile counterparts. While this highlights the potential involvement of LIF in infertility, LIF is a multifaceted cytokine which plays additional roles in the maintenance of cell stemness and immunomodulation. Thus, we sought to explore the implications of LIF production within ectopic lesions on endometriosis pathophysiology. Through immunohistochemistry of an endometrioma tissue microarray and ELISA of tissue protein extract and peritoneal fluid samples, we identify LIF protein expression in the ectopic lesion microenvironment. Targeted RT qPCR for LIF and associated signaling transcripts, identify LIF to be significantly downregulated in the ectopic tissue compared to eutopic and control while its receptor, LIFR, is upregulated, highlighting a discordance in ectopic protein and mRNA LIF expression. In vitro treatment of endometriosis representative cell lines (12Z and hESC) with LIF increased production of immune-recruiting cytokines (MCP-1, MCP-3) and the angiogenic factor, VEGF, as well as stimulated tube formation in human umbilical vein endothelial cells (HUVECs). Finally, LIF treatment in a syngeneic mouse model of endometriosis induced both local and peripheral alterations to immune cell phenotypes, ultimately reducing immunoregulatory CD206+ small peritoneal macrophages and T regulatory cells. These findings suggest that LIF is present in the ectopic lesions of endometriosis patients and could be contributing to lesion vascularization and immunomodulation.
    Keywords:  cytokine; endometriosis; immunomodulation; infertility; leukemia inhibitory factor (LIF); vascularization
    DOI:  https://doi.org/10.3389/fimmu.2023.1089098
  3. Int Immunopharmacol. 2023 Apr 08. pii: S1567-5769(23)00467-8. [Epub ahead of print]118 110146
    AMPK reduces macrophage endotoxin tolerance through inhibition of TGF-β1 production and its signaling pathway.
    Mei Yin, Joungmin Kim, Jeong-Il Choi, Joon-Suk Bom, Hong-Beom Bae, Seongtae Jeong.
      Adenosine monophosphate-activated protein kinase (AMPK) is involved in suppression of the development of endotoxin tolerance, which is a driver of the immunosuppression induced by sepsis. However, the mechanism by which AMPK inhibits the development of endotoxin tolerance has not been clearly elucidated. Therefore, the present study was performed to investigate the mechanism by which the AMPK activator, metformin, inhibits the development of endotoxin tolerance. Lipopolysaccharide (LPS) increased the production of transforming growth factor (TGF)-β1 in macrophages, which was inhibited by metformin and resveratrol. Knockdown of AMPKα1 inhibited the suppressive effect of metformin on LPS-induced TGF-β1 production. TGF-β neutralizing antibody and TGF-β type I receptor inhibitor increased the production of TNF-α and IL-6 via LPS restimulation in tolerized macrophages. LPS increased Smad2 phosphorylation, but this was inhibited in cells treated with TGF-β neutralizing antibody or metformin. Smad2 knockdown inhibited the development of endotoxin tolerance, as evidenced by increased TNF-α production in response to LPS restimulation in tolerized macrophages. TGF-β1 expression was increased, and the levels of TNF-α and IL-6 production induced by LPS stimulation were decreased, in splenocytes of cecal ligation and puncture (CLP) model mice compared to sham-operated controls. However, metformin treatment suppressed the production of TGF-β1, and enhanced the production of TNF-α and IL-6 induced by LPS stimulation in splenocytes of CLP mice. These results indicated that AMPK activation inhibits LPS-induced TGF-β1 production and its signaling pathway, thus suppressing the development of endotoxin tolerance in macrophages.
    Keywords:  AMP-activated protein kinase; Lipopolysaccharide; Macrophage; Metformin; Tolerance
    DOI:  https://doi.org/10.1016/j.intimp.2023.110146
  4. Int Immunopharmacol. 2023 Apr 12. pii: S1567-5769(23)00470-8. [Epub ahead of print]119 110149
    Growth differentiation factor 15 protects the airway by inhibiting cell pyroptosis in obese asthmatic mice through the phosphoinositide 3-kinase/AKT pathway.
    Na Li, Fanghan He, Yunxiao Shang.
      Obese asthma is a form of refractory asthma with inflammation as the underlying mechanism. The specific mechanism of action of anti-inflammatory growth differentiation factor 15 (GDF15) in obese asthma is unclear. The purpose of this study was to explore the effect of GDF15 on cell pyroptosis in obese asthma and to determine its mechanism of airway protection. Male C57BL6/J mice were fed with a high-fat diet, sensitized, and challenged with ovalbumin. Recombinant human (rh)GDF15 was administered 1 h before the challenge. GDF15 treatment significantly reduced airway inflammatory cell infiltration, mucus hypersecretion and airway resistant, and decreased cell counts and inflammatory factors in bronchoalveolar lavage fluid. Serum inflammatory factors decreased, and the increased levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and gasdermin-D (GSDMD-N) in obese asthmatic mice were inhibited. Furthermore, the suppressed phosphoinositide 3-kinase (PI3K)/AKT signal pathway was activated after rhGDF15 treatment. The same result was obtained by overexpression of GDF15 in human bronchial epithelial cells induced by lipopolysaccharide (LPS) in vitro, and the effect of GDF15 was reversed after the application of a PI3K pathway inhibitor. Thus, GDF15 could protect the airway by inhibiting cell pyroptosis in obese asthmatic mice through the PI3K/AKT signaling pathway.
    Keywords:  GDF15; Inflammation; Obese asthma; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2023.110149
  5. JCI Insight. 2023 Apr 10. pii: e165867. [Epub ahead of print]8(7):
    Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations.
    Jeremy M Robbins, Prashant Rao, Shuliang Deng, Michelle J Keyes, Usman A Tahir, Daniel H Katz, Pierre M Jean Beltran, François Marchildon, Jacob L Barber, Bennet Peterson, Yan Gao, Adolfo Correa, James G Wilson, J Gustav Smith, Paul Cohen, Robert Ross, Claude Bouchard, Mark A Sarzynski, Robert E Gerszten.
      Regular exercise leads to widespread salutary effects, and there is increasing recognition that exercise-stimulated circulating proteins can impart health benefits. Despite this, limited data exist regarding the plasma proteomic changes that occur in response to regular exercise. Here, we perform large-scale plasma proteomic profiling in 654 healthy human study participants before and after a supervised, 20-week endurance exercise training intervention. We identify hundreds of circulating proteins that are modulated, many of which are known to be secreted. We highlight proteins involved in angiogenesis, iron homeostasis, and the extracellular matrix, many of which are novel, including training-induced increases in fibroblast activation protein (FAP), a membrane-bound and circulating protein relevant in body-composition homeostasis. We relate protein changes to training-induced maximal oxygen uptake adaptations and validate our top findings in an external exercise cohort. Furthermore, we show that FAP is positively associated with survival in 3 separate, population-based cohorts.
    Keywords:  Cardiology; Cardiovascular disease; Extracellular matrix; Metabolism; Proteomics
    DOI:  https://doi.org/10.1172/jci.insight.165867
  6. Front Oncol. 2023 ;13 1025443
    Glucocorticoid mediated inhibition of LKB1 mutant non-small cell lung cancers.
    Kenneth E Huffman, Long Shan Li, Ryan Carstens, Hyunsil Park, Luc Girard, Kimberley Avila, Shuguang Wei, Rahul Kollipara, Brenda Timmons, Jessica Sudderth, Nawal Bendris, Jiyeon Kim, Pamela Villalobos, Junya Fujimoto, Sandra Schmid, Ralph J Deberardinis, Ignacio Wistuba, John Heymach, Ralf Kittler, Esra A Akbay, Bruce Posner, Yuzhuo Wang, Stephen Lam, Steven A Kliewer, David J Mangelsdorf, John D Minna.
      The glucocorticoid receptor (GR) is an important anti-cancer target in lymphoid cancers but has been understudied in solid tumors like lung cancer, although glucocorticoids are often given with chemotherapy regimens to mitigate side effects. Here, we identify a dexamethasone-GR mediated anti-cancer response in a subset of aggressive non-small cell lung cancers (NSCLCs) that harbor Serine/Threonine Kinase 11 (STK11/LKB1) mutations. High tumor expression of carbamoyl phosphate synthase 1 (CPS1) was strongly linked to the presence of LKB1 mutations, was the best predictor of NSCLC dexamethasone (DEX) sensitivity (p < 10-16) but was not mechanistically involved in DEX sensitivity. Subcutaneous, orthotopic and metastatic NSCLC xenografts, biomarker-selected, STK11/LKB1 mutant patient derived xenografts, and genetically engineered mouse models with KRAS/LKB1 mutant lung adenocarcinomas all showed marked in vivo anti-tumor responses with the glucocorticoid dexamethasone as a single agent or in combination with cisplatin. Mechanistically, GR activation triggers G1/S cell cycle arrest in LKB1 mutant NSCLCs by inducing the expression of the cyclin-dependent kinase inhibitor, CDKN1C/p57(Kip2). All findings were confirmed with functional genomic experiments including CRISPR knockouts and exogenous expression. Importantly, DEX-GR mediated cell cycle arrest did not interfere with NSCLC radiotherapy, or platinum response in vitro or with platinum response in vivo. While DEX induced LKB1 mutant NSCLCs in vitro exhibit markers of cellular senescence and demonstrate impaired migration, in vivo DEX treatment of a patient derived xenograft (PDX) STK11/LKB1 mutant model resulted in expression of apoptosis markers. These findings identify a previously unknown GR mediated therapeutic vulnerability in STK11/LKB1 mutant NSCLCs caused by induction of p57(Kip2) expression with both STK11 mutation and high expression of CPS1 as precision medicine biomarkers of this vulnerability.
    Keywords:  LKB1; glucocorticoid; lung cancer; nuclear receptor; targeted therapy
    DOI:  https://doi.org/10.3389/fonc.2023.1025443
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