bims-stacyt 2022-10-09 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2022‒10‒09
nine papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.
Adipocyte coculture induces a pro-inflammatory, fibrotic, angiogenic, and proliferative microenvironment in uterine leiomyoma cells.
Macrophage functionality in obesity favors cancer progression.
Emerging roles of purinergic signaling in anti-cancer therapy resistance.
Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.
LP07 and LLC pre-clinical models of lung cancer induce divergent anabolic deficits and expression of pro-inflammatory effectors of muscle wasting.
Establishment of lactate-metabolism-related signature to predict prognosis and immunotherapy response in patients with colon adenocarcinoma.
CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis.
MTAP deficiency contributes to immune landscape remodeling and tumor evasion.

Nat Metab. 2022 Oct 03.

GAB functions as a bioenergetic and signalling gatekeeper to control T cell inflammation.

Siwen Kang, Lingling Liu, Tingting Wang, Matthew Cannon, Penghui Lin, Teresa W-M Fan, David A Scott, Hsin-Jung Joyce Wu, Andrew N Lane, Ruoning Wang.

γ-Aminobutyrate (GAB), the biochemical form of (GABA) γ-aminobutyric acid, participates in shaping physiological processes, including the immune response. How GAB metabolism is controlled to mediate such functions remains elusive. Here we show that GAB is one of the most abundant metabolites in CD4+ T helper 17 (TH17) and induced T regulatory (iTreg) cells. GAB functions as a bioenergetic and signalling gatekeeper by reciprocally controlling pro-inflammatory TH17 cell and anti-inflammatory iTreg cell differentiation through distinct mechanisms. 4-Aminobutyrate aminotransferase (ABAT) funnels GAB into the tricarboxylic acid (TCA) cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activity in iTreg cells enables GAB to be exported to the extracellular environment where it acts as an autocrine signalling metabolite that promotes iTreg cell differentiation. Accordingly, ablation of ABAT activity in T cells protects against experimental autoimmune encephalomyelitis (EAE) progression. Conversely, ablation of GABAA receptor in T cells worsens EAE. Our results suggest that the cell-autonomous control of GAB on CD4+ T cells is bimodal and consists of the sequential action of two processes, ABAT-dependent mitochondrial anaplerosis and the receptor-dependent signalling response, both of which are required for T cell-mediated inflammation.

DOI: https://doi.org/10.1038/s42255-022-00638-1
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 28. pii: S0925-4439(22)00235-6. [Epub ahead of print] 166564

Adipocyte coculture induces a pro-inflammatory, fibrotic, angiogenic, and proliferative microenvironment in uterine leiomyoma cells.

Sadia Afrin, Malak El Sabah, Ahmed Manzoor, Mariko Miyashita-Ishiwata, Lauren Reschke, Mostafa A Borahay.

  OBJECTIVE: Obesity and its consequences are among the biggest challenges facing the healthcare system. Uterine leiomyomas are the most common gynecologic tumors. The risk of leiomyoma increases with obesity, but the underlying mechanisms of this association remain unclear. The aim of the present study to determine the cellular and molecular mechanisms by which adipocyte contributes to both leiomyoma tumor initiation and promotion.METHODS: Primary myometrium and leiomyoma cells were isolated from patients who underwent a hysterectomy or myomectomy. Pro-inflammatory, fibrotic, and angiogenic factors were measured using a multiplex cytokine array in human primary and immortalized myometrial and leiomyoma cells cocultured with human adipocyte (SW872) cells, or in animal ELT3 leiomyoma cells cocultured with 3 T3-L1 adipocytes. The free fatty acids (FFAs) and fatty acid-binding protein 4 (FABP4) levels were measured using immunofluorescence assays. Other protein abundances were determined using western blots. The expression levels of TNF-α, MCP-1, phospho-NF-κB, TGFβ3 and VEGF-A in lean and obese in different leiomyoma patients were determined by immunofluorescence staining.
RESULTS: Adipocytes promote inflammation, fibrosis, and angiogenesis in uterine leiomyoma cells by upregulating associated factors, such as IL-1β, TNF-α, MCP-1, GM-CSF, TGF-βs, PLGF, VEGF, HB-EGF, G-CSF and FGF2. Coculture led to the transfer of FFAs and FABP4 from adipocytes to leiomyoma cells, suggesting that adipocytes may modulate metabolic activity in these tumor cells. Increased levels of FFA and FABP4 expressions were detected in obese leiomyoma tissue compared to lean. The adipocyte-leiomyoma cell interaction increased the phospho-NF-κB level, which plays a key role in inflammation, restructuring metabolic pathways, and angiogenesis. Obese leiomyoma patients expressed a higher amount of TNF-α, MCP-1, phospho-NF-κB, TGFβ3 and VEGF-A than lean leiomyoma patients, consistent with in vitro findings. Furthermore, we found that adipocyte secretory factors enhance leiomyoma cell proliferation by increasing PCNA abundance. Finally, the inhibition of the inflammatory factors TNF-α, MCP-1, and NF-κB abrogated the adipocyte coculture-induced proliferation of leiomyoma cells.
CONCLUSIONS: Adipocytes release inflammatory, fibrotic, and angiogenic factors, along with FFAs, which contribute to a tumor-friendly microenvironment that may promote leiomyoma growth and can represent a new target for leiomyoma prevention and treatment.

Keywords:  Adipocyte; Angiogenesis; Fibrosis; Inflammation; Proliferation; Uterine leiomyoma

DOI:  https://doi.org/10.1016/j.bbadis.2022.166564
Cancer Res. 2022 Oct 03. pii: CAN-22-1257. [Epub ahead of print]

Macrophage functionality in obesity favors cancer progression.

Abhijeet Singh, Shyamananda Singh Mayengbam, Himanshi Yaduvanshi, Mohan R Wani, Manoj Kumar Bhat.

Obesity has a profound influence on the progression of many diseases. It induces multi-factorial effects such as dyslipidemia, insulin resistance, diabetes, arterial hypertension, and increased incidences of cancers. Multiple mechanisms link obesity with cancer initiation and progression; however, the least studied is the role of macrophages. Nutritional overload causes adipose tissue expansion in obesity and alters the balance between pro- and anti-inflammatory macrophages, which becomes a primary cause of inflammation. The chronic low-grade inflammation driven by macrophages is also an important characteristic of cancer. Adipose tissue secretes various adipokines, namely adiponectin, leptin, IL-6, TNF-α, etc., which influence macrophage behavior and tumor progression. Furthermore, other metabolic effects of obesity, such as hyperlipidemia, hyperglycemia, and hypercholesterolemia, can also regulate macrophage functionality towards tumor cells. This review summarizes events and mechanisms by which obesity influences macrophage-tumor cell interactions. The role of macrophages in anti-cancer therapies under obese conditions, as well as the effect of macrophages on T cells to regulate tumor progression, are also highlighted.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1257
Front Cell Dev Biol. 2022 ;10 1006384

Emerging roles of purinergic signaling in anti-cancer therapy resistance.

Michele Zanoni, Anna Pegoraro, Elena Adinolfi, Elena De Marchi.

  Cancer is a complex disease with a rapid growing incidence and often characterized by a poor prognosis. Although impressive advances have been made in cancer treatments, resistance to therapy remains a critical obstacle for the improvement of patients outcome. Current treatment approaches as chemo-, radio-, and immuno-therapy deeply affect the tumor microenvironment (TME), inducing an extensive selective pressure on cancer cells through the activation of the immune system, the induction of cell death and the release of inflammatory and damage-associated molecular patterns (DAMPS), including nucleosides (adenosine) and nucleotides (ATP and ADP). To survive in this hostile environment, resistant cells engage a variety of mitigation pathways related to metabolism, DNA repair, stemness, inflammation and resistance to apoptosis. In this context, purinergic signaling exerts a pivotal role being involved in mitochondrial function, stemness, inflammation and cancer development. The activity of ATP and adenosine released in the TME depend upon the repertoire of purinergic P2 and adenosine receptors engaged, as well as, by the expression of ectonucleotidases (CD39 and CD73) on tumor, immune and stromal cells. Besides its well established role in the pathogenesis of several tumors and in host-tumor interaction, purinergic signaling has been recently shown to be profoundly involved in the development of therapy resistance. In this review we summarize the current advances on the role of purinergic signaling in response and resistance to anti-cancer therapies, also describing the translational applications of combining conventional anticancer interventions with therapies targeting purinergic signaling.

Keywords:  ATP; CD39; CD73; P2 receptors; adenosine; adenosine receptors; cancer therapy resistance

DOI:  https://doi.org/10.3389/fcell.2022.1006384
Oncogene. 2022 Oct 04.

Non-genomic activation of the AKT-mTOR pathway by the mitochondrial stress response in thyroid cancer.

Woo Kyung Lee Doolittle, Sunmi Park, Seul Gi Lee, Seonhyang Jeong, Gibbeum Lee, Dongryeol Ryu, Kristina Schoonjans, Johan Auwerx, Jandee Lee, Young Suk Jo.

Cancer progression is associated with metabolic reprogramming and causes significant intracellular stress; however, the mechanisms that link cellular stress and growth signalling are not fully understood. Here, we identified a mechanism that couples the mitochondrial stress response (MSR) with tumour progression. We demonstrated that the MSR is activated in a significant proportion of human thyroid cancers via the upregulation of heat shock protein D family members and the mitokine, growth differentiation factor 15. Our study also revealed that MSR triggered AKT/S6K signalling by activating mTORC2 via activating transcription factor 4/sestrin 2 activation whilst promoting leucine transporter and nutrient-induced mTORC1 activation. Importantly, we found that an increase in mtDNA played an essential role in MSR-induced mTOR activation and that crosstalk between MYC and MSR potentiated mTOR activation. Together, these findings suggest that the MSR could be a predictive marker for aggressive human thyroid cancer as well as a useful therapeutic target.

DOI: https://doi.org/10.1038/s41388-022-02484-7
J Appl Physiol (1985). 2022 Oct 06.

LP07 and LLC pre-clinical models of lung cancer induce divergent anabolic deficits and expression of pro-inflammatory effectors of muscle wasting.

Daniel J Belcher, Maria Guitart, Brian Hain, Hyo-Gun Kim, David Waning, Esther Barreiro, Gustavo A Nader.

  Pre-clinical models have been instrumental to elucidate the mechanisms underlying muscle wasting in lung cancer (LC). We investigated anabolic deficits and the expression of pro-inflammatory effectors of muscle wasting in the LP07 and Lewis lung carcinoma (LLC) tumor models. Tumor growth resulted in significant weakness in LP07 but not in LLC mice despite similar reductions in gastrocnemius muscle mass in both models. The LP07 tumors caused a reduction in ribosomal (r)RNA and a decrease in rRNA gene (rDNA) transcription elongation, while no changes in ribosomal capacity were evident in LLC tumor bearing mice. Expression of RNA Polymerase I (Pol I) elongation-associated subunits Polr2f, PAF53, and Znrd1 mRNAs was significantly elevated in the LP07 model, while Pol I elongation-related factors FACT and Spt4/5 mRNAs were elevated in the LLC mice. Reductions in RPS6 and 4E-BP1 phosphorylation were similar in both models but was independent of mTOR phosphorylation in LP07 mice. Muscle inflammation was also tumor-specific, IL-6 and TNF-α mRNA increased with LLC tumors, but upregulation of NLRP3 mRNA was independent of tumor type. In summary, while both models caused muscle wasting, only the LP07 model displayed muscle weakness with reductions in ribosomal capacity. Intracellular signaling diverged at the mTOR level with similar reductions in RPS6 and 4E-BP1 phosphorylation regardless of tumor type. The increase in pro-inflammatory factors was more pronounced in the LLC model. Our results demonstrate novel divergent anabolic deficits and expression of pro-inflammatory effectors of muscle wasting in the LP07 and LLC pre-clinical models of lung cancer.

Keywords:  cachexia; inflammation; lung cancer; muscle wasting; ribosomal RNA

DOI:  https://doi.org/10.1152/japplphysiol.00246.2022
Front Oncol. 2022 ;12 958221

Establishment of lactate-metabolism-related signature to predict prognosis and immunotherapy response in patients with colon adenocarcinoma.

Zhengrong Zou, Yongjie Chai, Qi Li, Xuan Lin, Qingfang He, Qiusheng Xiong.

  The outcome of colon adenocarcinoma (COAD) patients remains dismal, and lactate metabolism has been characterized to promote tumor development and immune evasion. Based on the above background, it is worthwhile to explore novel prognostic and therapeutic biomarkers for COAD patients from the aspect of lactate metabolism. Above all, 228 available lactate-metabolism-related genes (LMRGs) were acquired, and the landscape of copy number variation and the expression difference of mRNA levels between colon normal and tumor samples were investigated among these LMRGs. Importantly, eight overall survival (OS)-involved LMRGs were then distinguished by means of univariate Cox regression analysis in both GSE40967 and TCGA-COAD data sets. Subsequently, prognostic risk scores were established, integrating seven OS-related LMRGs by LASSO Cox regression analysis in the GSE40967 set, and then verified in the TCGA-COAD cohort. From the comprehensive analyses, COAD patients with high risk had comparatively more inferior survival probability in all populations of the study, and they tended to have more severe clinicopathological features with the risk score increasing. Moreover, by integrating age, AJCC T and pathological stage, and risk score, we constructed a prognostic nomogram that demonstrated great prediction effectiveness for OS of COAD patients. Furthermore, the potential effect of various risk score on tumor immune was assessed from enrichment of immune-related pathways, tumor-infiltrating immune cells, and expression levels of immune checkpoints separately. We could draw a conclusion that COAD patients with higher lactate-metabolism-related risk scores may acquire an immunosuppressive tumor microenvironment, which subsequently led to immune escapes and poor prognoses. Conclusively, all findings in the present study illustrate a great prognostic value of the lactate-metabolism-related risk signature, providing more in-depth insights into the indispensable function of lactate metabolism in prognosis and tumor immunity of COAD.

Keywords:  colon adenocarcinoma; immunotherapy; lactate metabolism; risk signature; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.958221
Nat Commun. 2022 Oct 02. 13(1): 5782

CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis.

Ping Yang, Hong Qin, Yiyu Li, Anhua Xiao, Enze Zheng, Han Zeng, Chunxiao Su, Xiaoqing Luo, Qiannan Lu, Meng Liao, Lei Zhao, Li Wei, Zac Varghese, John F Moorhead, Yaxi Chen, Xiong Z Ruan.

Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis.

DOI: https://doi.org/10.1038/s41467-022-33349-y
Immunology. 2022 Oct 01.

MTAP deficiency contributes to immune landscape remodeling and tumor evasion.

Wen-Hsin Chang, Ssu-Wei Hsu, Jun Zhang, Ji-Min Li, David D Yang, Chih-Wei Chu, Estelle E Yoo, Weici Zhang, Sung-Liang Yu, Ching-Hsien Chen.

  Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumor progression due to MTAP loss are yet to be elucidated. Utilizing integrated analyses of the transcriptome, proteome, and secretome, we demonstrated that MTAP deficiency alters tumor-intrinsic, immune-related pathways and reprograms cytokine profiles toward a tumor-favorable environment. Additionally, MTAP-knockout cells exhibited a marked increase in the immune checkpoint protein PD-L1. Upon co-culturing primary T cells with cancer cells, MTAP loss-mediated PD-L1 upregulation inhibited T cell-mediated killing activity and induced several T cell exhaustion markers. In two xenograft tumor models, we showed a modest increase in average volume of tumors derived from MTAP-deficient cells than that of MTAP-proficient tumors. Surprisingly, a remarkable increase in tumor size was observed in humanized mice bearing MTAP-deficient tumors, as compared to their MTAP-expressing counterparts. Following immunophenotypic characterization of tumor-infiltrating leukocytes by mass cytometry analysis, MTAP-deficient tumors were found to display decreased immune infiltrates with lower proportions of both T lymphocytes and natural killer cells and higher proportions of immunosuppressive cells as compared to MTAP-expressing tumor xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumor immune microenvironment, promoting tumor progression and immune evasion. This article is protected by copyright. All rights reserved.

Keywords:  CyTOF; PD-L1; humanized mice; immunosuppression; tumor suppressor

DOI:  https://doi.org/10.1111/imm.13587