bims-stacyt 2023-10-22 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–10–22
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.
Metabolic advantages of regulatory T cells dictated by cancer cells.
Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops.
Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma.
Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.
Unraveling the hypoxia modulating potential of VEGF family genes in pan-cancer.
Delivery of adipose-derived growth factors from heparinized adipose acellular matrix accelerates wound healing.
Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer.
Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling.
Fatty Acids Increase GDF15 and Reduce Food Intake Through a GFRAL Signaling Axis.

Curr Opin Biotechnol. 2023 Oct 18. pii: S0958-1669(23)00118-0. [Epub ahead of print]84 103008

Nucleotide metabolism in the regulation of tumor microenvironment and immune cell function.

Helena B Madsen, Marlies Jw Peeters, Per Thor Straten, Claus Desler.

Nucleotide metabolism plays a crucial role in the regulation of the tumor microenvironment (TME) and immune cell function. In the TME, limited availability of nucleotide precursors due to increased consumption by tumor cells and T cells affects both tumor development and immune function. Metabolic reprogramming in tumor cells favors pathways supporting growth and proliferation, including nucleotide synthesis. Additionally, extracellular nucleotides, such as ATP and adenosine, exhibit dual roles in modulating immune function and tumor cell survival. ATP stimulates antitumor immunity by activating purinergic receptors, while adenosine acts as a potent immunosuppressor. Targeting nucleotide metabolism in the TME holds immense promise for cancer therapy. Understanding the intricate relationship between nucleotide metabolism, the TME, and immune responses will pave the way for innovative therapeutic interventions.

DOI: https://doi.org/10.1016/j.copbio.2023.103008
Int Immunol. 2023 Oct 14. pii: dxad035. [Epub ahead of print]

Metabolic advantages of regulatory T cells dictated by cancer cells.

Masaki Kondo, Shogo Kumagai, Hiroyoshi Nishikawa.

  Cancer cells employ glycolysis for their survival and growth (the 'Warburg effect'). Consequently, surrounding cells including immune cells in the tumor microenvironment (TME) are exposed to hypoglycemic, hypoxic, and low pH circumstances. Since effector T cells depend on the glycolysis for their survival and functions, the metabolically harsh TME established by cancer cells is unfavorable, resulting in the impairment of effective antitumor immune responses. By contrast, immunosuppressive cells such as regulatory T (Treg) cells can infiltrate, proliferate, survive, and exert immunosuppressive functions in the metabolically harsh TME, indicating the different metabolic dependance between effector T cells and Treg cells. Indeed, some metabolites that are harmful for effector T cells can be utilized by Treg cells; lactic acid, a harmful metabolite for effector T cells, is available for Treg cell proliferation and functions. Deficiency of amino acids such as tryptophan and glutamine in the TME impairs effector T cell activation but increases Treg cell populations. Furthermore, hypoxia upregulates fatty acid oxidation via hypoxia-inducible factor 1α (HIF-1α) and promotes Treg cell migration. Adenosine is induced by the ectonucleotidases CD39 and CD73, which are strongly induced by HIF-1α, and reportedly accelerates Treg cell development by upregulating Foxp3 expression in T cells via A2AR-mediated signals. Therefore, this review focuses on the current views of the unique metabolism of Treg cells dictated by cancer cells. In addition, potential cancer combination therapies with immunotherapy and metabolic molecularly targeted reagents that modulate Treg cells in the TME are discussed to develop 'immune metabolism-based precision medicine'.

Keywords:  metabolism; regulatory T cell

DOI:  https://doi.org/10.1093/intimm/dxad035
Nucleic Acids Res. 2023 Oct 16. pii: gkad858. [Epub ahead of print]

Hypoxia-induced transcriptional stress is mediated by ROS-induced R-loops.

Tiffany S Ma, Katja R Worth, Conor Maher, Natalie Ng, Chiara Beghè, Natalia Gromak, Anna M Rose, Ester M Hammond.

Hypoxia is a common feature of solid tumors and is associated with poor patient prognosis, therapy resistance and metastasis. Radiobiological hypoxia (<0.1% O2) is one of the few physiologically relevant stresses that activates both the replication stress/DNA damage response and the unfolded protein response. Recently, we found that hypoxia also leads to the robust accumulation of R-loops, which led us to question here both the mechanism and consequence of hypoxia-induced R-loops. Interestingly, we found that the mechanism of R-loop accumulation in hypoxia is dependent on non-DNA damaging levels of reactive oxygen species. We show that hypoxia-induced R-loops play a critical role in the transcriptional stress response, evidenced by the repression of ribosomal RNA synthesis and the translocation of nucleolin from the nucleolus into the nucleoplasm. Upon depletion of R-loops, we observed a rescue of both rRNA transcription and nucleolin translocation in hypoxia. Mechanistically, R-loops accumulate on the rDNA in hypoxia and promote the deposition of heterochromatic H3K9me2 which leads to the inhibition of Pol I-mediated transcription of rRNA. These data highlight a novel mechanistic insight into the hypoxia-induced transcriptional stress response through the ROS-R-loop-H3K9me2 axis. Overall, this study highlights the contribution of transcriptional stress to hypoxia-mediated tumorigenesis.

DOI: https://doi.org/10.1093/nar/gkad858
J Hepatol. 2023 Oct 12. pii: S0168-8278(23)05170-X. [Epub ahead of print]

Endothelial DGKG promotes tumor angiogenesis and immune evasion in hepatocellular carcinoma.

Liren Zhang, Jiali Xu, Suiqing Zhou, Feifan Yao, Ruizhi Zhang, Wenhua You, Kai Yu, Yu Zhang, Tasiken Baheti, Liyong Pu, Jing Xu, Xiaofeng Qian, Yongxiang Xia, Xinzheng Dai, Qing Li, Xuehao Wang.

   BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is among the most prevalent and fatal cancers worldwide. The tumor microenvironment (TME) contributes to the poor response of patients with HCC to current therapies, while tumor vascular endothelial cells (ECs) are fundamental TME components significantly contributing to tumor progression. However, the specific functions and mechanisms of tumor vascular ECs in HCC remains unclear.
METHODS: We screened and validated the specific diacylglycerol kinase gamma (DGKG) hyper-expression in HCC tumor vascular ECs. Single-cell RNA sequencing (scRNA-seq), cytometry by time-of-flight (CyTOF), and in vitro and in vivo studies were performed to investigate the functions and mechanisms of endothelial DGKG. Multiplexed immunohistochemistry (mIHC) staining and flow cytometry were used to evaluate changes in the TME.
RESULTS: Functionally, endothelial DGKG promotes tumor angiogenesis and immunosuppressive regulatory T (Treg) cell differentiation in HCC. Of significance, we found that hypoxia-inducible factor-1α (HIF-1α) activates DGKG transcription by directly binding to its promoter region under hypoxia. Upregulated DGKG promotes HCC progression by recruiting ubiquitin specific peptidase 16 (USP16) to facilitate zinc finger E-box-binding homeobox 2 (ZEB2) deubiquitination and cytokine transforming growth factor-beta 1 (TGF-β1) positive feedback loop resultant activation, thus inducing tumor angiogenesis and Treg differentiation. Importantly, targeting endothelial DGKG potentiated the efficiency of dual blockade of PD-1 and VEGFR-2.
CONCLUSION: Hypoxia-induced EC-specific DGKG hyper-expression promotes tumor angiogenesis and immune evasion via the ZEB2/TGF-β1 axis, suggesting EC-specific DGKG as a potential therapeutic target for HCC.

Keywords:  Angiogenesis; Anti-angiogenic therapy; Hypoxia; Immunosuppression; Immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jhep.2023.10.006
Cancer Cell. 2023 Oct 16. pii: S1535-6108(23)00328-8. [Epub ahead of print]

Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring.

Lauren E Colbert, Molly B El Alam, Rui Wang, Tatiana Karpinets, David Lo, Erica J Lynn, Timothy A Harris, Jacob H Elnaggar, Kyoko Yoshida-Court, Katarina Tomasic, Julianna K Bronk, Julie Sammouri, Ananta V Yanamandra, Adilene V Olvera, Lily G Carlin, Travis Sims, Andrea Y Delgado Medrano, Tatiana Cisneros Napravnik, Madison O'Hara, Daniel Lin, Chike O Abana, Hannah X Li, Patricia J Eifel, Anuja Jhingran, Melissa Joyner, Lilie Lin, Lois M Ramondetta, Andrew M Futreal, Kathleen M Schmeler, Geena Mathew, Stephanie Dorta-Estremera, Jianhua Zhang, Xiaogang Wu, Nadim J Ajami, Matthew Wong, Cullen Taniguchi, Joseph F Petrosino, K Jagannadha Sastry, Pablo C Okhuysen, Sara A Martinez, Lin Tan, Iqbal Mahmud, Philip L Lorenzi, Jennifer A Wargo, Ann H Klopp.

  Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.

Keywords:  cervical cancer; chemoradiation; lactate; metabolism; microbiome; radiation

DOI:  https://doi.org/10.1016/j.ccell.2023.09.012
Genomics Inform. 2023 Sep 27.

Unraveling the hypoxia modulating potential of VEGF family genes in pan-cancer.

So-Hyun Bae, Taewon Hwang, Mi-Ryung Han.

  Tumor hypoxia, oxygen deprivation state, occurs in most cancers and promotes angiogenesis, enhancing the potential for metastasis. The vascular endothelial growth factor (VEGF) family genes play crucial roles in tumorigenesis by promoting angiogenesis. To investigate the malignant processes triggered by hypoxia-induced angiogenesis across pan-cancers, we comprehensively analyzed the relationships between the expression of VEGF family genes and hypoxic microenvironment based on integrated bioinformatics methods. Our results suggest that the expression of VEGF family genes differs significantly among various cancers, highlighting their heterogeneity effect on human cancers. Across the 33 cancers, VEGFB and VEGFD showed the highest and lowest expression levels, respectively. The survival analysis showed that VEGFA and placental growth factor (PGF) were correlated with poor prognosis in many cancers, including kidney renal cell and liver hepatocellular carcinoma. VEGFC expression was positively correlated with glioma and stomach cancer. VEGFA and PGF showed distinct positive correlations with hypoxia scores in most cancers, indicating a potential correlation with tumor aggressiveness. The expression of miRNAs targeting VEGF family genes, including hsa-miR-130b-5p and hsa-miR-940, was positively correlated with hypoxia. In immune subtypes analysis, VEGFC was highly expressed in C3 (inflammatory) and C6 (transforming growth factor β dominant) across various cancers, indicating its potential role as a tumor promotor. VEGFC expression exhibited positive correlations with immune infiltration scores, suggesting low tumor purity. High expression of VEGFA and VEGFC showed favorable responses to various drugs, including BLU-667, which abrogates RET signaling, an oncogenic driver in liver and thyroid cancers. Our findings suggest potential roles of VEGF family genes in malignant processes related with hypoxia-induced angiogenesis.

Keywords:  angiogenesis, pan-cancer, tumor hypoxia, VEGF family genes

DOI:  https://doi.org/10.5808/gi.23061
Front Bioeng Biotechnol. 2023 ;11 1270618

Delivery of adipose-derived growth factors from heparinized adipose acellular matrix accelerates wound healing.

Jiangjiang Ru, Qian Zhang, Shaowei Zhu, Junrong Cai, Yunfan He, Feng Lu.

  Dermal white adipocytes are closely associated with skin homeostasis and wound healing. However, it has not been fully investigated whether adipose-derived products improve wound healing. Here, we obtained adipose acellular matrix (AAM) and adipose-derived growth factors (ADGFs) from human adipose tissue and fabricated an ADGF-loaded AAM via surface modification with heparin. The product, HEP-ADGF-AAM, contained an adipose-derived scaffold and released ADGFs in a controlled fashion. To test its efficacy in promoting wound healing, mice with full thickness wound received three different treatments: HEP-ADGF-AAM, AAM and ADM. Control mice received no further treatments. Among these treatments, HEP-ADGF-AAM best improved wound healing. It induced adipogenesis in situ after in vivo implantation and provided an adipogenic microenvironment for wounds by releasing ADGFs. HEP-ADGF-AAM not only induced adipocyte regeneration, but also enhanced fibroblast migration, promoted vessel formation, accelerated wound closure, and enhanced wound epithelialization. Moreover, there was a close interaction between HEP-ADGF-AAM and the wound bed, and collagen was turned over in HEP-ADGF-AAM. These results show that HEP-ADGF-AAM might substantially improve re-epithelialization, angiogenesis, and skin appendage regeneration, and is thus a promising therapeutic biomaterial for skin wound healing.

Keywords:  acellular dermal matrix; adipocyte; decellularized adipose tissue; growth factor; wound healing

DOI:  https://doi.org/10.3389/fbioe.2023.1270618
J Immunother Cancer. 2023 Oct;pii: e007310. [Epub ahead of print]11(10):

Increased interleukin-6/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non-small cell lung cancer.

Abdul Rafeh Naqash, Justin D McCallen, Emma Mi, Sanna Iivanainen, Mona A Marie, Daria Gramenitskaya, James Clark, Jussi Pekka Koivunen, Shravanti Macherla, Sweta Jonnalagadda, Shanker Polsani, Rahim Ali Jiwani, Maida Hafiz, Mahvish Muzaffar, Leonardo Brunetti, Chipman R G Stroud, Paul R Walker, Kun Wang, Youngmin Chung, Eytan Ruppin, Se-Hoon Lee, Li V Yang, David J Pinato, Joo Sang Lee, Alessio Cortellini.

   BACKGROUND: Systemic immune activation, hallmarked by C-reactive protein (CRP) and interleukin-6 (IL-6), can modulate antitumor immune responses. In this study, we evaluated the role of IL-6 and CRP in the stratification of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). We also interrogated the underlying immunosuppressive mechanisms driven by the IL-6/CRP axis.
METHODS: In cohort A (n=308), we estimated the association of baseline CRP with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in patients with NSCLC treated with ICIs alone or with chemo-immunotherapy (Chemo-ICI). Baseline tumor bulk RNA sequencing (RNA-seq) of lung adenocarcinomas (LUADs) treated with pembrolizumab (cohort B, n=59) was used to evaluate differential expression of purine metabolism, as well as correlate IL-6 expression with PFS. CODEFACS approach was applied to deconvolve cohort B to characterize the tumor microenvironment by reconstructing the cell-type-specific transcriptome from bulk expression. Using the LUAD cohort from The Cancer Genome Atlas (TCGA) we explored the correlation between IL-6 expression and adenosine gene signatures. In a third cohort (cohort C, n=18), plasma concentrations of CRP, adenosine 2a receptor (A2aR), and IL-6 were measured using ELISA.
RESULTS: In cohort A, 67.2% of patients had a baseline CRP≥10 mg/L (CRP-H). Patients with CRP-H achieved shorter OS (8.6 vs 14.8 months; p=0.006), shorter PFS (3.3 vs 6.6 months; p=0.013), and lower ORR (24.7% vs 46.3%; p=0.015). After adjusting for relevant clinical variables, CRP-H was confirmed as an independent predictor of increased risk of death (HR 1.51, 95% CI: 1.09 to 2.11) and lower probability of achieving disease response (OR 0.34, 95% CI: 0.13 to 0.89). In cohort B, RNA-seq analysis demonstrated higher IL-6 expression on tumor cells of non-responders, along with a shorter PFS (p<0.05) and enrichment of the purinergic pathway. Within the TCGA LUAD cohort, tumor IL-6 expression strongly correlated with the adenosine signature (R=0.65; p<2.2e-16). Plasma analysis in cohort C demonstrated that CRP-H patients had a greater median baseline level of A2aR (6.0 ng/mL vs 1.3 ng/mL; p=0.01).
CONCLUSIONS: This study demonstrates CRP as a readily available blood-based prognostic biomarker in ICI-treated NSCLC. Additionally, we elucidate a potential link of the CRP/IL-6 axis with the immunosuppressive adenosine signature pathway that could drive inferior outcomes to ICIs in NSCLC and also offer novel therapeutic avenues.

Keywords:  Adenosine; Immune Checkpoint Inhibitors; Inflammation; Lung Neoplasms; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007310
Cell Death Dis. 2023 Oct 14. 14(10): 681

Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling.

Ilaria Petraroia, Patrizia Ghidotti, Giulia Bertolini, Francesca Pontis, Luca Roz, Melissa Balsamo, Paola Suatoni, Ugo Pastorino, Anna Maria Ferretti, Gabriella Sozzi, Orazio Fortunato.

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRASV12), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133+CXCR4+ metastasis initiating cells (MICs) in HBEC-sh-p53-KRASV12high cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRASV12high cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.

DOI: https://doi.org/10.1038/s41419-023-06212-1
Diabetes. 2023 Oct 17. pii: db230495. [Epub ahead of print]

Fatty Acids Increase GDF15 and Reduce Food Intake Through a GFRAL Signaling Axis.

Dongdong Wang, Maria Joy Therese Jabile, Junfeng Lu, Logan K Townsend, Celina M Valvano, Jaya Gautam, Battsetseg Batchuluun, Evangelia E Tsakiridis, James S V Lally, Gregory R Steinberg.

In contrast to the well-defined biological feedback loops controlling glucose, the mechanisms by which the body responds to changes in fatty acid availability are less clearly defined. GDF15 suppresses the consumption of diets high in fat but is paradoxically increased in obese mice fed a high-fat diet. Given this interrelationship, we investigated whether diets high in fat could directly increase GDF15 independently of obesity. We found that fatty acids increase GDF15 levels dose-dependently with the greatest response observed with linolenic acid. GDF15 mRNA expression was modestly increased in the gastrointestinal tract, however, kidney GDF15 mRNA was ~1000-fold higher and was increased by over 3-fold with subsequent RNAscope analysis showing elevated expression within the cortex and outer medulla. Treatment of wildtype mice with linolenic acid reduced food intake and body mass, however, this effect was disappeared in mice lacking the GDF15 receptor GFRAL. An equal caloric load of glucose did not suppress food intake or reduce body mass in either WT or GFRAL KO mice. These data indicate that fatty acids such as linolenic acid increases GDF15 and suppresses food intake through a mechanism requiring GFRAL. These data suggest that a primary physiological function of GDF15 may be as a fatty acid sensor designed to protect cells from fatty acid overload.

DOI: https://doi.org/10.2337/db23-0495