bims-stacyt 2022-03-06 papers

bims-stacyt

Biomed News

on Paracrine crosstalk between cancer and the organism

Issue of 2022‒03‒06
nine papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

PERK is a critical metabolic hub for immunosuppressive function in macrophages.
The Unfolded Protein Response at the Tumor-Immune Interface.
Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages.
Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance.
Senescent macrophages in the human adipose tissue as a source of inflammaging.
Tumor microenvironment remodeling modulates macrophage phenotype in breast cancer lymphangiogenesis.
Human endothelial cells promote arsenic-transformed lung epithelial cells to induce tumor growth and angiogenesis through interleukin-8 induction.
Extracellular ATP promotes breast cancer chemoresistance via HIF-1α signaling.
Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulating the IL-6/JAK signaling pathway.

Nat Immunol. 2022 Feb 28.

PERK is a critical metabolic hub for immunosuppressive function in macrophages.

Lydia N Raines, Haoxin Zhao, Yuzhu Wang, Heng-Yi Chen, Hector Gallart-Ayala, Pei-Chun Hsueh, Wei Cao, Yeojung Koh, Ana Alamonte-Loya, Pu-Ste Liu, Julijana Ivanisevic, Chan-Wang Jerry Lio, Ping-Chih Ho, Stanley Ching-Cheng Huang.

Chronic inflammation triggers compensatory immunosuppression to stop inflammation and minimize tissue damage. Studies have demonstrated that endoplasmic reticulum (ER) stress augments the suppressive phenotypes of immune cells; however, the molecular mechanisms underpinning this process and how it links to the metabolic reprogramming of immunosuppressive macrophages remain elusive. In the present study, we report that the helper T cell 2 cytokine interleukin-4 and the tumor microenvironment increase the activity of a protein kinase RNA-like ER kinase (PERK)-signaling cascade in macrophages and promote immunosuppressive M2 activation and proliferation. Loss of PERK signaling impeded mitochondrial respiration and lipid oxidation critical for M2 macrophages. PERK activation mediated the upregulation of phosphoserine aminotransferase 1 (PSAT1) and serine biosynthesis via the downstream transcription factor ATF-4. Increased serine biosynthesis resulted in enhanced mitochondrial function and α-ketoglutarate production required for JMJD3-dependent epigenetic modification. Inhibition of PERK suppressed macrophage immunosuppressive activity and could enhance the efficacy of immune checkpoint programmed cell death protein 1 inhibition in melanoma. Our findings delineate a previously undescribed connection between PERK signaling and PSAT1-mediated serine metabolism critical for promoting immunosuppressive function in M2 macrophages.

DOI: https://doi.org/10.1038/s41590-022-01145-x
Front Immunol. 2022 ;13 823157

The Unfolded Protein Response at the Tumor-Immune Interface.

Maurizio Zanetti, Su Xian, Magalie Dosset, Hannah Carter.

  The tumor-immune interface has surged to primary relevance in an effort to understand the hurdles facing immune surveillance and cancer immunotherapy. Reports over the past decades have indicated a role for the unfolded protein response (UPR) in modulating not only tumor cell fitness and drug resistance, but also local immunity, with emphasis on the phenotype and altered function of immune cells such as myeloid cells and T cells. Emerging evidence also suggests that aneuploidy correlates with local immune dysregulation. Recently, we reported that the UPR serves as a link between aneuploidy and immune cell dysregulation in a cell nonautonomous way. These new findings add considerable complexity to the organization of the tumor microenvironment (TME) and the origin of its altered function. In this review, we summarize these data and also discuss the role of aneuploidy as a negative regulator of local immunity.

Keywords:  T cells; aneuploidy; myeloid cells; transcellular stress; unfolded protein response (UPR)

DOI:  https://doi.org/10.3389/fimmu.2022.823157
Cell Metab. 2022 Mar 01. pii: S1550-4131(22)00046-8. [Epub ahead of print]34(3): 487-501.e8

Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages.

Marah C Runtsch, Stefano Angiari, Alexander Hooftman, Ridhima Wadhwa, Yanling Zhang, Yunan Zheng, Joseph S Spina, Melanie C Ruzek, Maria A Argiriadi, Anne F McGettrick, Rui Santalla Mendez, Alessia Zotta, Christian G Peace, Aoife Walsh, Roberta Chirillo, Emily Hams, Padraic G Fallon, Ranjith Jayamaran, Kamal Dua, Alexandra C Brown, Richard Y Kim, Jay C Horvat, Philip M Hansbro, Chu Wang, Luke A J O'Neill.

  The Krebs cycle-derived metabolite itaconate and its derivatives suppress the inflammatory response in pro-inflammatory "M1" macrophages. However, alternatively activated "M2" macrophages can take up itaconate. We therefore examined the effect of itaconate and 4-octyl itaconate (OI) on M2 macrophage activation. We demonstrate that itaconate and OI inhibit M2 polarization and metabolic remodeling. Examination of IL-4 signaling revealed inhibition of JAK1 and STAT6 phosphorylation by both itaconate and OI. JAK1 activation was also inhibited by OI in response to IL-13, interferon-β, and interferon-γ in macrophages and in T helper 2 (Th2) cells. Importantly, JAK1 was directly modified by itaconate derivatives at multiple residues, including cysteines 715, 816, 943, and 1130. Itaconate and OI also inhibited JAK1 kinase activity. Finally, OI treatment suppressed M2 macrophage polarization and JAK1 phosphorylation in vivo. We therefore identify itaconate and OI as JAK1 inhibitors, suggesting a new strategy to inhibit JAK1 in M2 macrophage-driven diseases.

Keywords:  Jak-STAT; Krebs cycle; M2 macrophage; immunometabolism; itaconate; macrophages

DOI:  https://doi.org/10.1016/j.cmet.2022.02.002
EMBO J. 2022 Mar 03. e109890

Endothelium-derived lactate is required for pericyte function and blood-brain barrier maintenance.

Heon-Woo Lee, Yanying Xu, Xiaolong Zhu, Cholsoon Jang, Woosung Choi, Hosung Bae, Weiwei Wang, Liqun He, Suk-Won Jin, Zoltan Arany, Michael Simons.

  Endothelial cells differ from other cell types responsible for the formation of the vascular wall in their unusual reliance on glycolysis for most energy needs, which results in extensive production of lactate. We find that endothelium-derived lactate is taken up by pericytes, and contributes substantially to pericyte metabolism including energy generation and amino acid biosynthesis. Endothelial-pericyte proximity is required to facilitate the transport of endothelium-derived lactate into pericytes. Inhibition of lactate production in the endothelium by deletion of the glucose transporter-1 (GLUT1) in mice results in loss of pericyte coverage in the retina and brain vasculatures, leading to the blood-brain barrier breakdown and increased permeability. These abnormalities can be largely restored by oral lactate administration. Our studies demonstrate an unexpected link between endothelial and pericyte metabolisms and the role of endothelial lactate production in the maintenance of the blood-brain barrier integrity. In addition, our observations indicate that lactate supplementation could be a useful therapeutic approach for GLUT1 deficiency metabolic syndrome patients.

Keywords:  BBB permeability; Glucose; endothelial metabolism; lactate; pericyte metabolism

DOI:  https://doi.org/10.15252/embj.2021109890
Geroscience. 2022 Mar 05.

Senescent macrophages in the human adipose tissue as a source of inflammaging.

Giulia Matacchione, Jessica Perugini, Eleonora Di Mercurio, Jacopo Sabbatinelli, Francesco Prattichizzo, Martina Senzacqua, Gianluca Storci, Christian Dani, Giovanni Lezoche, Mario Guerrieri, Antonio Giordano, Massimiliano Bonafè, Fabiola Olivieri.

  Obesity is a major risk factor for type 2 diabetes and a trigger of chronic and systemic inflammation. Recent evidence suggests that an increased burden of senescent cells (SCs) in the adipose tissue of obese/diabetic animal models might underlie such pro-inflammatory phenotype. However, the role of macrophages as candidate SCs, their phenotype, the distribution of SCs among fat depots, and clinical relevance are debated. The senescence marker β-galactosidase and the macrophage marker CD68 were scored in visceral (vWAT) and subcutaneous (scWAT) adipose tissue from obese patients (n=17) undergoing bariatric surgery and control patients (n=4) subjected to cholecystectomy. A correlation was made between the number of SCs and BMI, serum insulin, and the insulin resistance (IR) index HOMA. The monocyte cell line (THP-1) was cultured in vitro in high glucose milieu (60 mM D-glucose) and subsequently co-cultured with human adipocytes (hMADS) to investigate the reciprocal inflammatory activation. In obese patients, a significantly higher number of SCs was observed in vWAT compared to scWAT; about 70% of these cells expressed the macrophage marker CD68; and the number of SCs in vWAT, but not in scWAT, positively correlated with BMI, HOMA-IR, and insulin. THP-1 cultured in vitro in high glucose milieu acquired a senescent-like phenotype (HgSMs), characterized by a polarization toward a mixed M1/M2-like secretory phenotype. Co-culturing HgSMs with hMADS elicited pro-inflammatory cytokine expression in both cell types, and defective insulin signaling in hMADS. In morbid obesity, expansion of visceral adipose depots involves an increased burden of macrophages with senescent-like phenotype that may promote a pro-inflammatory profile and impair insulin signaling in adipocytes, supporting a framework where senescent macrophages fuel obesity-induced systemic inflammation and possibly contribute to the development of IR.

Keywords:  Adipose tissue; Inflammaging; Insulin resistance; Macrophage; Obesity; Senescent cell

DOI:  https://doi.org/10.1007/s11357-022-00536-0
FASEB J. 2022 Apr;36(4): e22248

Tumor microenvironment remodeling modulates macrophage phenotype in breast cancer lymphangiogenesis.

Yan Du, Manlin Cao, Yiwen Liu, Yiqing He, Cuixia Yang, Guoliang Zhang, Youben Fan, Feng Gao.

  Hyaluronan (HA) is dynamically remodeled in tumor microenvironment (TME) and is reported to be closely related to tumor lymphatic metastasis by inducing lymphangiogenesis. Macrophages are known to be involved in neo-lymphatic vessels formation. However, few studies have investigated the role of HA-mediated TME remodeling on macrophages-dependent lymphangiogenesis. We previously showed that HA could drive macrophages to acquire the M2 phenotype. In this study, we attempt to study the crosstalk between HA in TME and macrophages dependent lymphangiogenesis. First, we found that the abundant assembly of HA in breast cancer tissue was accompanied by increased infiltration of macrophages featured by expressing lymphatic endothelial markers. Then, to further identify the remodeling of HA in regulating macrophage phenotype, we used HA fragments which are usually enriched in TME for this purpose. Our results showed that the reconstructed HA could induce bone marrow-derived macrophages (BMDMs) to express markers of lymphatic endothelium and form tube-like structures, suggesting a novel function of HA from TME on macrophages-dependent lymphangiogenesis. Finally, we found that inhibition of the HA-TLR4 pathway could reduce the ability of BMDMs to exhibit lymphatic endothelial phenotype. Our results provide new insight into tumor microenvironment remodeling and macrophages in breast cancer lymphangiogenesis.

Keywords:  LMW-HA; bone marrow-derived macrophages; hyaluronan remodeling; lymphangiogenesis; tumor microenvironment

DOI:  https://doi.org/10.1096/fj.202101230R
Aging (Albany NY). 2022 Mar 03. 14(undefined):

Human endothelial cells promote arsenic-transformed lung epithelial cells to induce tumor growth and angiogenesis through interleukin-8 induction.

Lei Zhao, Yi-Fang Wang, Jie Liu, Bing-Hua Jiang, Ling-Zhi Liu.

  Arsenic exposure is associated with lung cancer. Angiogenesis is essential for tumor development. However, the role and mechanism of human vascular endothelial cells in tumor growth and angiogenesis induced by arsenic-transformed bronchial epithelial (As-T) cells remain to be elucidated. In this study, we found that endothelial cells significantly increased As-T cell-induced tumor growth compared to those induced by As-T cells alone. To understand the molecular mechanism, we found that endothelial cells co-cultured with As-T cells or cultured in conditioned medium (CM) prepared from As-T cells showed much higher cell migration, proliferation, and tube formation compared to those co-cultured with BEAS-2B (B2B) cells or cultured in CM from B2B. We identified that higher levels of intracellular interleukin 8 (IL-8) were secreted by As-T cells, which activated IL-8/IL-8R signaling to promote endothelial cells migration and tube formation. IL-8 silencing and knockout (KO) in As-T cells, or IL-8 neutralizing antibody dramatically suppressed endothelial cell proliferation, migration, tube formation in vitro, and tumor growth and angiogenesis in vivo, suggesting a key role of IL-8 in As-T cells to induce angiogenesis via a paracrine effect. Finally, blocking of IL-8 receptors C-X-C chemokine receptor type 1 (CXCR1) and CXCR2 with neutralizing antibodies and chemical inhibitors inhibited tube formation, indicating that IL-8Rs on endothelial cells are necessary for As-T cell-induced angiogenesis. Overall, this study reveals an important molecular mechanism of arsenic-induced carcinogenesis, and suggests a new option to prevent and treat arsenic-induced angiogenesis.

Keywords:  IL-8; angiogenesis; arsenic; lung cancer; paracrine

DOI:  https://doi.org/10.18632/aging.203930
Cell Death Dis. 2022 Mar 02. 13(3): 199

Extracellular ATP promotes breast cancer chemoresistance via HIF-1α signaling.

Hui Yang, Yue-Hang Geng, Peng Wang, Hong-Quan Zhang, Wei-Gang Fang, Xin-Xia Tian.

We have previously demonstrated that extracellular adenosine 5'-triphosphate (ATP) promotes breast cancer cell chemoresistance. However, the underlying mechanism remains unclear. Using a cDNA microarray, we demonstrated that extracellular ATP can stimulate hypoxia-inducible factor (HIF) signaling. In this study, we report that hypoxia-inducible factor 1α (HIF-1α) was upregulated after ATP treatment and mediated the ATP-driven chemoresistance process. We aimed to investigate the mechanisms and identify potential clinically relevant targets that are involved. Using mass spectrometry, we found that aldolase A (ALDOA) interacts with HIF-1α and increases HIF-1α expression. We then demonstrated that STAT3-ALDOA mediates ATP-HIF-1α signaling and upregulates the HIF-1 target genes adrenomedullin (ADM) and phosphoinositide-dependent kinase-1 (PDK1). Moreover, we show that PI3K/AKT acts upstream of HIF-1α in ATP signaling and contributes to chemoresistance in breast cancer cells. In addition, HIF-1α-knockdown or treatment with direct HIF inhibitors combined with the ATP hydrolase apyrase in MDA-MB-231 cells induced enhanced drug sensitivity in nude BALB/c mice. We then used in vitro spheroid formation assays to demonstrate the significance of ATP-HIF-1α in mediating chemoresistance. Furthermore, considering that indirect HIF inhibitors are effective in clinical cancer therapy, we treated tumor-bearing BALB/c mice with STAT3 and PI3K/AKT inhibitors and found that the dual-targeting strategy sensitized breast cancer to cisplatin. Finally, using breast cancer tissue microarrays, we found that ATP-HIF-1α signaling is associated with cancer progression, poor prognosis, and resistance to chemotherapy. Taken together, we suggest that HIF-1α signaling is vital in ATP-driven chemoresistance and may serve as a potential target for breast cancer therapies.

DOI: https://doi.org/10.1038/s41419-022-04647-6
Biochem Biophys Res Commun. 2022 Feb 03. pii: S0006-291X(22)00179-6. [Epub ahead of print]600 130-135

Glycerophospholipid metabolism is involved in rheumatoid arthritis pathogenesis by regulating the IL-6/JAK signaling pathway.

Jiang Su, Shilin Li, Jianghua Chen, Congcong Jian, Jiarui Hu, Hongjia Du, Huanyue Hai, Jianhong Wu, Fanxin Zeng, Jing Zhu, Yi Liu.

  To explore the metabolic mechanism of differential plasma interleukin (IL)-6 expression in patients with rheumatoid arthritis (RA). A total of 240 RA patients were enrolled in the non-target metabolomics study cohort and 69 healthy volunteers were included as healthy controls (HCs). Plasma IL-6 levels were detected by electrochemiluminescence assay. Plasma metabolites were detected by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Patients with active RA (n = 20) and remissive RA (n = 20) and 20 HCs were enrolled in the targeted validation cohort. Metabolites identified by non-target metabolomics were quantitatively analyzed by ultra-performance liquid chromatography-triple quadrupole tandem mass spectrometry. Effects of 1-oleoyl-sn-glycero-3-phosphocholine (OGPC) associated with IL-6 on MH7A cells were assessed. After 24-h or 48-h induction by TNF-α, the supernatants were collected for IL-6 quantification by enzyme-linked immunosorbent assay. Furthermore, Western blot was performed to investigate the relative JAK2 and p-JAK2 expressions. With an increasing IL-6 level, OGPC shown to be related to the glycerophospholipid metabolism pathway by Kyoto Encyclopedia of Genes and Genomes analysis displayed a significant decrease. In the validating RA cohort, the OGPC concentrations in remissive RA group and active RA group decreased compared with HC group. OGPC down-regulated IL-6 secretion and p-JAK2 expression in TNF-α-induced MH7A cells in vitro. In conclusion, glycerophospholipid metabolism is the main metabolic pathway associated with the differential IL-6 expression in RA patients. The down-regulated OGPC is a promoting factor for the increased IL-6 plasma level in RA patients, which further affects the downstream JAK signaling pathway.

Keywords:  1-oleoyl-sn-glycero-3-phosphocholine; Glycerophospholipid metabolism; IL-6; JAK; Metabolomics; Rheumatoid arthritis

DOI:  https://doi.org/10.1016/j.bbrc.2022.02.003