bims-stacyt 2024-10-06 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–10–06
twelve papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment.
Identifying metabolic limitations in the tumor microenvironment.
Macrophages and T cells in metabolic disorder-associated cancers.
GDF15 and LCN2 for early detection and prognosis of pancreatic cancer.
Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response.
Activating transcription factor 4 plays a major role in shaping the transcriptional response to isoginkgetin in HCT116 cells.
The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.
Hypoxia-Induced Adaptations of N-Glycomes and Proteomes in Breast Cancer Cells and Their Secreted Extracellular Vesicles.
High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.
Remembering Hypoxia: Uncovering the Long-Term Effects of Transient Oxygen Deprivation on IFN Signaling and Progression of Breast Cancer.
O-GlcNAcylation: Crosstalk between Hemostasis, Inflammation, and Cancer.
An Overview of Research Advances in Oncology Regarding the Transcription Factor ATF4.

Cancer Res. 2024 Oct 02.

HIF1α Counteracts TGFβ1-Driven TSP1 Expression in Endothelial Cells to Stimulate Angiogenesis in the Hypoxic Tumor Microenvironment.

Yu-Wei Luo, Yang Fang, Hui-Xian Zeng, Yu-Chen Ji, Meng-Zhi Wu, Hui Li, Jie-Ying Chen, Li-Min Zheng, Jian-Hong Fang, Shi-Mei Zhuang.

Emerging evidence suggests that transforming growth factor β1 (TGFβ1) can inhibit angiogenesis, contradicting the coexistence of active angiogenesis and high abundance of TGFβ1 in the tumor microenvironment. Here, we investigated how tumors overcome the anti-angiogenic effect of TGFβ1. TGFβ1 treatment suppressed physiological angiogenesis in chick chorioallantoic membrane and zebrafish models but did not affect angiogenesis in mouse hepatoma xenografts. The suppressive effect of TGFβ1 on angiogenesis was recovered in mouse xenografts by a hypoxia-inducible factor 1α (HIF1α) inhibitor. In contrast, a HIF1α stabilizer abrogated angiogenesis in zebrafish, indicating that hypoxia may attenuate the anti-angiogenic role of TGFβ1. Under normoxic conditions, TGFβ1 inhibited angiogenesis by upregulating anti-angiogenic factor thrombospondin 1 (TSP1) in endothelial cells (ECs) via TGFβ type I receptor (TGFβR1)-SMAD2/3 signaling. In a hypoxic microenvironment, HIF1α induced microRNA-145 (miR145) expression; miR145 abolished the inhibitory effect of TGFβ1 on angiogenesis by binding and repressing SMAD2/3 expression and subsequently reducing TSP1 levels in ECs. Primary ECs isolated from human hepatocellular carcinoma (HCC) displayed increased miR145 and decreased SMAD3 and TSP1 compared to ECs from adjacent non-tumor livers. The reduced SMAD3 or TSP1 in ECs was associated with increased angiogenesis in HCC tissues. Collectively, this study identified that TGFβ1-TGFβR1-SMAD2/3-TSP1 signaling in ECs inhibits angiogenesis. This inhibition can be circumvented by a hypoxia-HIF1α-miR145 axis, elucidating a mechanism by which hypoxia promotes angiogenesis.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2324
Sci Adv. 2024 Oct 04. 10(40): eadq7305

Identifying metabolic limitations in the tumor microenvironment.

Guillaume Cognet, Alexander Muir.

Solid tumors are characterized by dysfunctional vasculature that limits perfusion and delivery of nutrients to the tumor microenvironment. Limited perfusion coupled with the high metabolic demand of growing tumors has led to the hypothesis that many tumors experience metabolic stress driven by limited availability of nutrients such as glucose, oxygen, and amino acids in the tumor. Such metabolic stress has important implications for the biology of cells in the microenvironment, affecting both disease progression and response to therapies. Recently, techniques have been developed to identify limiting nutrients and resulting metabolic stresses in solid tumors. These techniques have greatly expanded our understanding of the metabolic limitations in tumors. This review will discuss these experimental tools and the emerging picture of metabolic limitations in tumors arising from recent studies using these approaches.

DOI: https://doi.org/10.1126/sciadv.adq7305
Nat Rev Cancer. 2024 Oct 01.

Macrophages and T cells in metabolic disorder-associated cancers.

Daniel Taranto, Daan J Kloosterman, Leila Akkari.

Cancer and metabolic disorders have emerged as major global health challenges, reaching epidemic levels in recent decades. Often viewed as separate issues, metabolic disorders are shown by mounting evidence to heighten cancer risk and incidence. The intricacies underlying this connection are still being unraveled and encompass a complex interplay between metabolites, cancer cells and immune cells within the tumour microenvironment (TME). Here, we outline the interplay between metabolic and immune cell dysfunction in the context of three highly prevalent metabolic disorders, namely obesity; two associated liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH); and type 2 diabetes. We focus primarily on macrophages and T cells, the critical roles of which in dictating inflammatory response and immune surveillance in metabolic disorder-associated cancers are widely reported. Moreover, considering the ever-increasing number of patients prescribed with metabolism disorder-altering drugs and diets in recent years, we discuss how these therapies modulate systemic and local immune phenotypes, consequently impacting cancer malignancy. Collectively, unraveling the determinants of metabolic disorder-associated immune landscape and their role in fuelling cancer malignancy will provide a framework essential to therapeutically address these highly prevalent diseases.

DOI: https://doi.org/10.1038/s41568-024-00743-1
Transl Oncol. 2024 Sep 30. pii: S1936-5233(24)00256-0. [Epub ahead of print]50 102129

GDF15 and LCN2 for early detection and prognosis of pancreatic cancer.

Xinxia Zhu, Brennan Olson, Dove Keith, Mason A Norgard, Peter R Levasseur, Parham Diba, Sara Protzek, Ju Li, Xiaolin Li, Tetiana Korzun, Ariana L Sattler, Abigail C Buenafe, Aaron J Grossberg, Daniel L Marks.

   BACKGROUND: The prognosis of pancreatic ductal adenocarcinomas (PDAC) remains very poor, emphasizing the critical importance of early detection, where biomarkers offer unique potential. Although growth differentiation factor 15 (GDF15) and Lipocalin 2 (LCN2) have been linked to PDAC, their precise roles as biomarkers are uncertain.
METHODS: Circulating levels of GDF15 and LCN2 were examined in human PDAC patients, heathy controls, and individuals with benign pancreatic diseases. Circulating levels of IL-6, CA19-9, and neutrophil-to-lymphocyte ratio (NLR) were measured for comparisons. Correlations between PDAC progression and overall survival were assessed. A mouse PDAC model was employed for comprehensive analyses, complementing the human studies by exploring associations with various metabolic and inflammatory parameters. Sensitivity and specificity of the biomarkers were evaluated.
FINDINGS: Our results demonstrated elevated levels of circulating GDF15 and LCN2 in PDAC patients compared to both healthy controls and individuals with benign pancreatic diseases, with higher GDF15 levels associated with disease progression and increased mortality. In PDAC mice, circulating GDF15 and LCN2 progressively increased, correlating with tumor growth, behavioral manifestations, tissue and molecular pathology, and cachexia development. GDF15 exhibited highly sensitive and specific for PDAC patients compared to CA19-9, IL-6, or NLR, while LCN2 showed even greater sensitivity and specificity in PDAC mice. Combining GDF15 and LCN2, or GDF15 and CA19-9, enhanced sensitivity and specificity.
INTERPRETATION: Our findings indicate that GDF15 holds promise as a biomarker for early detection and prognosis of PDAC, while LCN2 could strengthen diagnostic panels.

Keywords:  Biomarker; Early detection; GDF15; LCN2; Pancreatic cancer; Prognosis

DOI:  https://doi.org/10.1016/j.tranon.2024.102129
Biochem Pharmacol. 2024 Sep 27. pii: S0006-2952(24)00560-4. [Epub ahead of print] 116560

Curcumol effectively improves obesity through GDF15 induction via activation of endoplasmic reticulum stress response.

Lin Wang, Jia-Jia Huang, Wei-Jia Zhu, Zhao-Kun Zhai, Chan Lin, Xiao Guan, Hai-Ping Liu, Tong Dou, Yi-Zhun Zhu, Xu Chen.

  The escalating prevalence of obesity presents a formidable global health challenge, underscoring the imperative for efficacious pharmacotherapeutic interventions. However, current anti-obesity medications often exhibit limited efficacy and adverse effects, necessitating the exploration of alternative therapeutic approaches. Growth differentiation factor 15 (GDF15) has emerged as a promising target for obesity management, given its crucial role in appetite control and metabolic regulation. In this study, we aimed to investigate the efficacy of curcumol, a sesquiterpene compound derived from plants of the Zingiberaceae family, in obesity treatment. Our findings demonstrate that curcumol effectively induces the expression of GDF15 through the activation of the endoplasmic reticulum stress pathway. To confirm the role of GDF15 as a critical target for curcumol's function, we compared the effects of curcumol in wild-type mice and Gdf15-knockout mice. Using a high-fat diet-induced obese murine model, we observed that curcumol led to reduced appetite and altered dietary preferences mediated by GDF15. Furthermore, chronic curcumol intervention resulted in promising anti-obesity effects. Additionally, curcumol administration improved glucose tolerance and lipid metabolism in the obese mice. These findings highlight the potential of curcumol as a GDF15 inducer and suggest innovative strategies for managing obesity and its associated metabolic disorders. In conclusion, our study provides evidence for the efficacy of curcumol in obesity treatment by inducing GDF15 expression. The identified effects of curcumol on appetite regulation, dietary preferences, glucose tolerance, and lipid metabolism emphasize its potential as a therapeutic agent for combating obesity and related metabolic disorders.

Keywords:  Curcumol; Endoplasmic reticulum stress; GDF15; High-fat diet; Metabolic disorders; Obesity

DOI:  https://doi.org/10.1016/j.bcp.2024.116560
Sci Rep. 2024 10 02. 14(1): 22938

Activating transcription factor 4 plays a major role in shaping the transcriptional response to isoginkgetin in HCT116 cells.

Erin van Zyl, John D H Stead, Claire Peneycad, Carole L Yauk, Bruce C McKay.

  Activating transcription factor 4 (ATF4) plays a central role in the integrated stress response (ISR) and one overlapping branch of the unfolded protein response (UPR). We recently reported that the splicing inhibitor isoginkgetin (IGG) induced ATF4 protein along with several known ATF4-regulated transcripts in a response that resembled the ISR and UPR. However, the contribution of ATF4-dependent and -independent transcriptional responses to IGG exposure was not known. Here we used RNA-sequencing in HCT116 colon cancer cells and an isogenic subline lacking ATF4 to investigate the contribution of ATF4 to IGG-induced changes in gene expression. Approximately 85% of the IGG-responsive DEGs in HCT116 cells were also differentially expressed in response to the ER stressor thapsigargin (Tg) and these were enriched for genes associated with the UPR and ISR. Most of these were positively regulated by IGG with impaired responses in the ATF4-deficient cells. Nonetheless, there were DEGs that responded similarly in both cell lines. The ATF4-independent IGG-induced DEGs included several metal responsive transcripts encoding metallothionines and a zinc transporter. Taken together, the predominant IGG response was ATF4-dependent in these cells and resembled the UPR and ISR while a second less prominent response involved the ATF4-independent regulation of metal responsive mRNAs.

Keywords:  ATF4; Endoplasmic reticulum stress; Integrated stress response; Isoginkgetin; Thapsigargin; Unfolded protein response

DOI:  https://doi.org/10.1038/s41598-024-74391-8
Biochim Biophys Acta Rev Cancer. 2024 Sep 26. pii: S0304-419X(24)00121-5. [Epub ahead of print]1879(6): 189190

The metabolic crosstalk of cancer-associated fibroblasts and tumor cells: Recent advances and future perspectives.

Bing Xia, Liqing Qiu, Jing Yue, Jingxing Si, Hongfang Zhang.

  Tumor cells grow in a microenvironment with a lack of nutrients and oxygen. Cancer-associated fibroblasts (CAFs) as one major component of tumor microenvironment have strong ability to survive under stressful conditions through metabolic remodelling. Furthermore, CAFs are educated by tumor cells and help them adapt to the hostile microenvironment through their metabolic communication. By inducing catabolism, CAFs release nutrients into the microenvironment which are taken up by tumor cells to satisfy their metabolic requirements. Furthermore, CAFs can recycle toxic metabolic wastes produced by cancer cells into energetic substances, allowing cancer cells to undergo biosynthesis. Their metabolic crosstalk also enhances CAFs' pro-tumor phenotype and reshape the microenvironment facilitating tumor cells' metastasis and immune escape. In this review, we have analyzed the effect and mechanisms of metabolic crosstalk between tumor cells and CAFs. We also analyzed the future perspectives in this area from the points of CAFs heterogeneity, spatial metabonomics and patient-derived tumor organoids (PDOs). These information may deepen the knowledge of tumor metabolism regulated by CAFs and provide novel insights into the development of metabolism-based anti-cancer strategies.

Keywords:  Anti-cancer strategies; CAFs; Environmental stress; Metabolic crosstalk; Tumor-promoting roles

DOI:  https://doi.org/10.1016/j.bbcan.2024.189190
Int J Mol Sci. 2024 Sep 23. pii: 10216. [Epub ahead of print]25(18):

Hypoxia-Induced Adaptations of N-Glycomes and Proteomes in Breast Cancer Cells and Their Secreted Extracellular Vesicles.

Bojia Peng, Kai Bartkowiak, Feizhi Song, Paula Nissen, Hartmut Schlüter, Bente Siebels.

  The hypoxic tumor microenvironment significantly impacts cellular behavior and intercellular communication, with extracellular vesicles (EVs) playing a crucial role in promoting angiogenesis, metastasis, and host immunosuppression, and presumed cancer progression and metastasis are closely associated with the aberrant surface N-glycan expression in EVs. We hypothesize that hypoxic tumors synthesize specific hypoxia-induced N-glycans in response to or as a consequence of hypoxia. This study utilized nano-LC-MS/MS to integrate quantitative proteomic and N-glycomic analyses of both cells and EVs derived from the MDA-MB-231 breast cancer cell line cultured under normoxic and hypoxic conditions. Whole N-glycome and proteome profiling revealed that hypoxia has an impact on the asparagine N-linked glycosylation patterns and on the glycolysis/gluconeogenesis proteins in cells in terms of altered N-glycosylation for their adaptation to low-oxygen conditions. Distinct N-glycan types, high-mannose glycans like Man3 and Man9, were highly abundant in the hypoxic cells. On the other hand, alterations in the sialylation and fucosylation patterns were observed in the hypoxic cells. Furthermore, hypoxia-induced EVs exhibit a signature consisting of mono-antennary structures and specific N-glycans (H4N3F1S2, H3N3F1S0, and H7N4F3S2; H8N4F1S0 and H8N6F1S2), which are significantly associated with poor prognoses for breast tumors, presumably altering the interactions within the tumor microenvironment to promote tumorigenesis and metastasis. Our findings provide an overview of the N-glycan profiles, particularly under hypoxic conditions, and offer insights into the potential biomarkers for tracking tumor microenvironment dynamics and for developing precision medicine approaches in oncology.

Keywords:  N-glycomics; N-glycosylation; extracellular vesicles; hypoxia; proteomics

DOI:  https://doi.org/10.3390/ijms251810216
Oncoimmunology. 2024 ;13(1): 2411070

High-grade serous ovarian cancer development and anti-PD-1 resistance is driven by IRE1α activity in neutrophils.

Alexander Emmanuelli, Camilla Salvagno, Sung-Min Hwang, Deepika Awasthi, Tito A Sandoval, Chang-Suk Chae, Jin-Gyu Cheong, Chen Tan, Takao Iwawaki, Juan R Cubillos-Ruiz.

  High-grade serious ovarian cancer (HGSOC) is an aggressive malignancy that remains refractory to current immunotherapies. While advanced stage disease has been extensively studied, the cellular and molecular mechanisms that promote early immune escape in HGSOC remain largely unexplored. Here, we report that primary HGSO tumors program neutrophils to inhibit T cell anti-tumor function by activating the endoplasmic reticulum (ER) stress sensor IRE1α. We found that intratumoral neutrophils exhibited overactivation of ER stress response markers compared with their counterparts at non-tumor sites. Selective deletion of IRE1α in neutrophils delayed primary ovarian tumor growth and extended the survival of mice with HGSOC by enabling early T cell-mediated tumor control. Notably, loss of IRE1α in neutrophils sensitized tumor-bearing mice to PD-1 blockade, inducing HGSOC regression and long-term survival in ~ 50% of the treated hosts. Hence, neutrophil-intrinsic IRE1α facilitates early adaptive immune escape in HGSOC and targeting this ER stress sensor might be used to unleash endogenous and immunotherapy-elicited immunity that controls metastatic disease.

Keywords:  ER stress; IRE1; PD-1 blockade; immunotherapy; neutrophils; ovarian cancer

DOI:  https://doi.org/10.1080/2162402X.2024.2411070
Cancer Res. 2024 Oct 01. 84(19): 3125-3127

Remembering Hypoxia: Uncovering the Long-Term Effects of Transient Oxygen Deprivation on IFN Signaling and Progression of Breast Cancer.

Stephen Connor Purdy, Heide L Ford.

Hypoxia occurs in 90% of solid tumors and is strongly associated with an increased propensity for metastasis. Hypoxia induces tumor progression largely through inducing HIF-mediated transcription, resulting in alterations to tumor cell metabolism, as well as increases in migration and invasion. Hypoxia also results in a myriad of changes to the tumor microenvironment (TME). While many studies have examined the immediate effects of hypoxia on tumor cells and the associated TME, far fewer have focused on the long-term consequences of transient reductions in oxygen. In this issue of Cancer Research, Iriondo and colleagues examined whether short-term exposure to hypoxia leads to a "hypoxic memory" in the context of breast cancer. The authors used established cell lines and circulating tumor cell lines to demonstrate that these cells harbor a hypoxic memory that sustains downregulation of IFN signaling and antigen presentation (AP) pathways that contribute to tumor progression via alterations to tumor cells and the TME. The authors further showed that cells that have experienced hypoxia maintain the reduction in IFN signaling in vivo and are more aggressive. They determined that the hypoxic memory and reduction of IFN signaling can be reversed with a histone deacetylase inhibitor, entinostat, providing a potential means to reverse hypoxia-induced suppression of IFN signaling. As suppression of IFN signaling has the potential to influence both tumor cells and the TME, the identification of a strategy to inhibit long-term suppression of IFN signaling downstream of hypoxia could prove to be an effective means to target tumor progression. See related article by Iriondo et al., p. 3141.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-2407
Int J Mol Sci. 2024 Sep 13. pii: 9896. [Epub ahead of print]25(18):

O-GlcNAcylation: Crosstalk between Hemostasis, Inflammation, and Cancer.

Itzel Patricia Vásquez Martínez, Eduardo Pérez-Campos, Laura Pérez-Campos Mayoral, Holanda Isabel Cruz Luis, María Del Socorro Pina Canseco, Edgar Zenteno, Irma Leticia Bazán Salinas, Margarito Martínez Cruz, Eduardo Pérez-Campos Mayoral, María Teresa Hernández-Huerta.

  O-linked β-N-acetylglucosamine (O-GlcNAc, O-GlcNAcylation) is a post-translational modification of serine/threonine residues of proteins. Alterations in O-GlcNAcylation have been implicated in several types of cancer, regulation of tumor progression, inflammation, and thrombosis through its interaction with signaling pathways. We aim to explore the relationship between O-GlcNAcylation and hemostasis, inflammation, and cancer, which could serve as potential prognostic tools or clinical predictions for cancer patients' healthcare and as an approach to combat cancer. We found that cancer is characterized by high glucose demand and consumption, a chronic inflammatory state, a state of hypercoagulability, and platelet hyperaggregability that favors thrombosis; the latter is a major cause of death in these patients. Furthermore, we review transcription factors and pathways associated with O-GlcNAcylation, thrombosis, inflammation, and cancer, such as the PI3K/Akt/c-Myc pathway, the nuclear factor kappa B pathway, and the PI3K/AKT/mTOR pathway. We also review infectious agents associated with cancer and chronic inflammation and potential inhibitors of cancer cell development. We conclude that it is necessary to approach both the diagnosis and treatment of cancer as a network in which multiple signaling pathways are integrated, and to search for a combination of potential drugs that regulate this signaling network.

Keywords:  O-GlcNAc; cancer; hemostasis; inflammation; post-translational modification

DOI:  https://doi.org/10.3390/ijms25189896
Curr Drug Targets. 2024 Sep 30.

An Overview of Research Advances in Oncology Regarding the Transcription Factor ATF4.

Yulu Chen, Qi Gao, Dan Wang, Xun Zou, Xiuming Li, Jing Ji, Bin Liu.

  This review provides a comprehensive overview of the recent advancements in research on ATF4 (Activating Transcription Factor 4) within the field of oncology. As a crucial transcription factor, ATF4 has garnered increasing attention for its role in cancer research. The review begins with an exploration of the regulatory mechanisms of ATF4, including its transcriptional control, post-translational modifications, and interactions with other transcription factors. It then highlights key research findings on ATF4's involvement in various aspects of tumor biology, such as cell proliferation, differentiation, apoptosis and survival, invasion and metastasis, and the tumor microenvironment. Furthermore, the review discusses the potential of targeting ATF4 as a novel therapeutic strategy for cancer treatment. It also explores how ATF4's interactions with existing anticancer drugs could inform the development of more effective therapeutic agents. By elucidating the role of ATF4 in tumor biology and its potential clinical applications, this review aims to provide new insights and strategies for cancer treatment.

Keywords:  ATF4; ER stress.; malignant; targeted therapy; transcription factor; tumor

DOI:  https://doi.org/10.2174/0113894501328461240921062056