bims-ecemfi 2024-04-21 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2024‒04‒21
sixteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Spatiotemporal architecture of immune cells and cancer-associated fibroblasts in high-grade serous ovarian carcinoma.
Emerging paradigms in cancer cell plasticity.
METTL3: Melting the tumor microenvironment for improved immunotherapy.
Evaluation of Tumorigenic Properties of MDA-MB-231 Cancer Stem Cells Cocultured with Telocytes and Telocyte-Derived Mitochondria Following miR-146a Inhibition.
Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNβ-HLA.
Electrophysiological and morphological modulation of neuronal-glial network by breast cancer and nontumorigenic mammary cell conditioned medium.
Glioblastoma mechanobiology at multiple length scales.
Cellular geometry and epithelial-mesenchymal plasticity intersect with PIEZO1 in breast cancer cells.
A Mathematical Model of TCR-T Cell Therapy for Cervical Cancer.
Tracking of Nascent Matrix Deposition during Muscle Stem Cell Activation across Lifespan Using Engineered Hydrogels.
Optical controlled and nuclear targeted CECR2 competitor to downregulate CSF-1 for metastatic breast cancer immunotherapy.
Characterizing heterogeneous single-cell dose responses computationally and experimentally using threshold inhibition surfaces and dose-titration assays.
Omental preadipocytes stimulate matrix remodeling and IGF signaling to support ovarian cancer metastasis.
Cancer-associated fibroblasts secrete FGF5 to inhibit ferroptosis to decrease cisplatin sensitivity in nasopharyngeal carcinoma through binding to FGFR2.
Crosstalk between lipid metabolism and EMT: emerging mechanisms and cancer therapy.
M2 Tumor-Associated Macrophages-Derived Exosomal MALAT1 Promotes Glycolysis and Gastric Cancer Progression.

Sci Adv. 2024 Apr 19. 10(16): eadk8805

Spatiotemporal architecture of immune cells and cancer-associated fibroblasts in high-grade serous ovarian carcinoma.

Alexander M Xu, Marcela Haro, Ann E Walts, Ye Hu, Joshi John, Beth Y Karlan, Akil Merchant, Sandra Orsulic.

High-grade serous ovarian carcinoma (HGSOC), the deadliest form of ovarian cancer, is typically diagnosed after it has metastasized and often relapses after standard-of-care platinum-based chemotherapy, likely due to advanced tumor stage, heterogeneity, and immune evasion and tumor-promoting signaling from the tumor microenvironment. To understand how spatial heterogeneity contributes to HGSOC progression and early relapse, we profiled an HGSOC tissue microarray of patient-matched longitudinal samples from 42 patients. We found spatial patterns associated with early relapse, including changes in T cell localization, malformed tertiary lymphoid structure (TLS)-like aggregates, and increased podoplanin-positive cancer-associated fibroblasts (CAFs). Using spatial features to compartmentalize the tissue, we found that plasma cells distribute in two different compartments associated with TLS-like aggregates and CAFs, and these distinct microenvironments may account for the conflicting reports about the role of plasma cells in HGSOC prognosis.

DOI: https://doi.org/10.1126/sciadv.adk8805
BMB Rep. 2024 Apr 17. pii: 6190. [Epub ahead of print]

Emerging paradigms in cancer cell plasticity.

Hyunbin D Huh, Hyun Woo Park.

Cancer cells metastasize to distant organs by altering their characteristics within the tumor microenvironment (TME) to effectively overcome challenges during the multistep tumorigenesis. Plasticity endows cancer cell with the capacity to shift between different states to invade, disseminate, and seed metastasis. The epithelial-to-mesenchymal transition (EMT) is a cellular program that abrogates cell-cell adhesions by EMT transcription factors (TF) and acquires mesenchymal features during cancer progression. On the other hand, adherent-to-suspension transition (AST) is an emerging theory that describes the acquisition of hematopoietic features by AST-TFs that can induce the reprogramming of anchorage dependency and promote cancer cell dissemination. The induction and plasticity of EMT and AST dynamically reprogram cell-cell and cell-matrix interaction during cancer dissemination and colonization. Here, we review the mechanisms governing cellular plasticity of AST and EMT during the metastatic cascade and discuss therapeutic challenges posed by these two morphological adaptations to provide insights for establishing new therapeutic interventions.
Cell Chem Biol. 2024 Apr 18. pii: S2451-9456(24)00121-1. [Epub ahead of print]31(4): 629-631

METTL3: Melting the tumor microenvironment for improved immunotherapy.

Longfei Gao, Lei Ding.

The tumor microenvironment (TME) dictates the outcome of cancer immunotherapy. In this issue of Cell Chemical Biology, Yu et al.1 report that targeting Mettl3 leads to a more inflamed, "hot" TME and effective anti-PD-1 therapy. This study points to a new target in remodeling the TME for improved immunotherapy.

DOI: https://doi.org/10.1016/j.chembiol.2024.03.005
DNA Cell Biol. 2024 Apr 18.

Evaluation of Tumorigenic Properties of MDA-MB-231 Cancer Stem Cells Cocultured with Telocytes and Telocyte-Derived Mitochondria Following miR-146a Inhibition.

Sena Babadag, Özlem Altundag-Erdogan, Yeliz Z Akkaya-Ulum, Betül Çelebi-Saltik.

  Telocytes have some cytoplasmic extensions called telopodes, which are thought to play a role in mitochondrial transfer in intercellular communication. Besides, it is hypothesized that telocytes establish cell membrane-mediated connections with breast cancer cells in coculture and may contribute to the survival of neoplastic cell clusters together with other stromal cells. The aim of this study is to investigate the contribution of telocytes and telocyte-derived mitochondria, which have also been identified in breast tumors, to the tumor development of breast cancer stem cells (CSCs) via miR-146a-5p. The isolation/characterization of telocytes from bone marrow mononuclear cells and the isolation of mitochondria from these cells were performed, respectively. In the next step, CSCs were isolated from the MDA-MB-231 cell line and were characterized. Then, miR-146a-5p expressions of CSCs were inhibited by anti-miR-146a-5p. The epithelial-mesenchymal transition (EMT) was determined by evaluating changes in vimentin protein levels and was evaluated by analyzing BRCA1, P53, SOX2, E-cadherin, and N-cadherin gene expression changes. Our results showed that miR-146a promoted stemness and oncogenic properties in CSCs. EMT (N-cadherin, vimentin, E-cadherin) and tumorigenic markers (BRCA1, P53, SOX2) of CSCs decreased after miR-146a inhibition. Bone marrow-derived telocytes and mitochondria derived from telocytes favored the reduction of CSC aggressiveness following this inhibition.

Keywords:  cancer stem cell; miR-146-5p; microRNA; mitochondria; telocyte

DOI:  https://doi.org/10.1089/dna.2024.0031
Adv Sci (Weinh). 2024 Apr 18. e2400888

Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNβ-HLA.

Ye Yi, Guihui Qin, Hongmei Yang, Hao Jia, Qibing Zeng, Dejin Zheng, Sen Ye, Zhiming Zhang, Tzu-Ming Liu, Kathy Qian Luo, Chu-Xia Deng, Ren-He Xu.

  Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-β (IFNβ) by MSCs. IFNβ reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.

Keywords:  cGAS‐STING‐IFNβ‐HLA pathway; circulating tumor cells; mesenchymal stromal cells; natural killer cells

DOI:  https://doi.org/10.1002/advs.202400888
Front Bioeng Biotechnol. 2024 ;12 1368851

Electrophysiological and morphological modulation of neuronal-glial network by breast cancer and nontumorigenic mammary cell conditioned medium.

Donatella Di Lisa, Katia Cortese, Michela Chiappalone, Pietro Arnaldi, Sergio Martinoia, Patrizio Castagnola, Laura Pastorino.

  Breast cancer is a significant global health concern, with the overexpression of human epidermal growth factor receptor 2 (HER2/ERBB2) being a driver oncogene in 20%-30% of cases. Indeed, HER2/ERBB2 plays a crucial role in regulating cell growth, differentiation, and survival via a complex signaling network. Overexpression of HER2/ERBB2 is associated with more aggressive behavior and increased risk of brain metastases, which remains a significant clinical challenge for treatment. Recent research has highlighted the role of breast cancer secretomes in promoting tumor progression, including excessive proliferation, immune invasion, and resistance to anti-cancer therapy, and their potential as cancer biomarkers. In this study, we investigated the impact of ERBB2+ breast cancer SKBR-3 cell line compared with MCF10-A mammary non-tumorigenic cell conditioned medium on the electrophysiological activity and morphology of neural networks derived from neurons differentiated from human induced pluripotent stem cells. Our findings provide evidence of active modulation of neuronal-glial networks by SKBR-3 and MCF10-A conditioned medium. These results provide insights into the complex interactions between breast cancer cells and the surrounding microenvironment. Further research is necessary to identify the specific factors within breast cancer conditioned medium that mediate these effects and to develop targeted therapies that disrupt this interaction.

Keywords:  HER2/ERBB2; breast cancer; electrophysiological activity; human induced pluripotent stem cells; secretome; tumor progression

DOI:  https://doi.org/10.3389/fbioe.2024.1368851
Biomater Adv. 2024 Apr 15. pii: S2772-9508(24)00103-1. [Epub ahead of print]160 213860

Glioblastoma mechanobiology at multiple length scales.

Raghu Vamsi Kondapaneni, Sumiran Kumar Gurung, Pinaki S Nakod, Kasra Goodarzi, Venu Yakati, Nicholas A Lenart, Shreyas S Rao.

  Glioblastoma multiforme (GBM), a primary brain cancer, is one of the most aggressive forms of human cancer, with a very low patient survival rate. A characteristic feature of GBM is the diffuse infiltration of tumor cells into the surrounding brain extracellular matrix (ECM) that provide biophysical, topographical, and biochemical cues. In particular, ECM stiffness and composition is known to play a key role in controlling various GBM cell behaviors including proliferation, migration, invasion, as well as the stem-like state and response to chemotherapies. In this review, we discuss the mechanical characteristics of the GBM microenvironment at multiple length scales, and how biomaterial scaffolds such as polymeric hydrogels, and fibers, as well as microfluidic chip-based platforms have been employed as tissue mimetic models to study GBM mechanobiology. We also highlight how such tissue mimetic models can impact the field of GBM mechanobiology.

Keywords:  Biomaterials; Glioblastoma; Mechanobiology; Stiffness

DOI:  https://doi.org/10.1016/j.bioadv.2024.213860
Commun Biol. 2024 Apr 17. 7(1): 467

Cellular geometry and epithelial-mesenchymal plasticity intersect with PIEZO1 in breast cancer cells.

Choon Leng So, Mélanie Robitaille, Francisco Sadras, Michael H McCullough, Michael J G Milevskiy, Geoffrey J Goodhill, Sarah J Roberts-Thomson, Gregory R Monteith.

Differences in shape can be a distinguishing feature between different cell types, but the shape of a cell can also be dynamic. Changes in cell shape are critical when cancer cells escape from the primary tumor and undergo major morphological changes that allow them to squeeze between endothelial cells, enter the vasculature, and metastasize to other areas of the body. A shift from rounded to spindly cellular geometry is a consequence of epithelial-mesenchymal plasticity, which is also associated with changes in gene expression, increased invasiveness, and therapeutic resistance. However, the consequences and functional impacts of cell shape changes and the mechanisms through which they occur are still poorly understood. Here, we demonstrate that altering the morphology of a cell produces a remodeling of calcium influx via the ion channel PIEZO1 and identify PIEZO1 as an inducer of features of epithelial-to-mesenchymal plasticity. Combining automated epifluorescence microscopy and a genetically encoded calcium indicator, we demonstrate that activation of the PIEZO1 force channel with the PIEZO1 agonist, YODA 1, induces features of epithelial-to-mesenchymal plasticity in breast cancer cells. These findings suggest that PIEZO1 is a critical point of convergence between shape-induced changes in cellular signaling and epithelial-mesenchymal plasticity in breast cancer cells.

DOI: https://doi.org/10.1038/s42003-024-06163-z
Bull Math Biol. 2024 Apr 16. 86(5): 57

A Mathematical Model of TCR-T Cell Therapy for Cervical Cancer.

Zuping Wang, Heyrim Cho, Peter Choyke, Doron Levy, Noriko Sato.

  Engineered T cell receptor (TCR)-expressing T (TCR-T) cells are intended to drive strong anti-tumor responses upon recognition of the specific cancer antigen, resulting in rapid expansion in the number of TCR-T cells and enhanced cytotoxic functions, causing cancer cell death. However, although TCR-T cell therapy against cancers has shown promising results, it remains difficult to predict which patients will benefit from such therapy. We develop a mathematical model to identify mechanisms associated with an insufficient response in a mouse cancer model. We consider a dynamical system that follows the population of cancer cells, effector TCR-T cells, regulatory T cells (Tregs), and "non-cancer-killing" TCR-T cells. We demonstrate that the majority of TCR-T cells within the tumor are "non-cancer-killing" TCR-T cells, such as exhausted cells, which contribute little or no direct cytotoxicity in the tumor microenvironment (TME). We also establish two important factors influencing tumor regression: the reversal of the immunosuppressive TME following depletion of Tregs, and the increased number of effector TCR-T cells with antitumor activity. Using mathematical modeling, we show that certain parameters, such as increasing the cytotoxicity of effector TCR-T cells and modifying the number of TCR-T cells, play important roles in determining outcomes.

Keywords:  Cervical cancer; Immunotherapy; Mathematical modeling; TCR-T cells; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11538-024-01261-9
Adv Biol (Weinh). 2024 Apr 14. e2400091

Tracking of Nascent Matrix Deposition during Muscle Stem Cell Activation across Lifespan Using Engineered Hydrogels.

Pamela Duran, Benjamin A Yang, Eleanor Plaster, Madeline Eiken, Claudia Loebel, Carlos A Aguilar.

  Adult stem cells occupy a niche that contributes to their function, but how stem cells rebuild their microenvironment after injury remains an open-ended question. Herein, biomaterial-based systems and metabolic labeling are utilized to evaluate how skeletal muscle stem cells deposit extracellular matrix. Muscle stem cells and committed myoblasts are observed to generate less nascent matrix than muscle resident fibro-adipogenic progenitors. When cultured on substrates that matched the stiffness of physiological uninjured and injured muscles, muscle stem cells increased nascent matrix deposition with activation kinetics. Reducing the ability to deposit nascent matrix by an inhibitor of vesicle trafficking (Exo-1) attenuated muscle stem cell function and mimicked impairments observed from muscle stem cells isolated from old muscles. Old muscle stem cells are observed to deposit less nascent matrix than young muscle stem cells, which is rescued with therapeutic supplementation of insulin-like growth factors. These results highlight the role of nascent matrix production with muscle stem cell activation.

Keywords:  biomaterials; extracellular matrix; hyaluronic acid; protein labeling; skeletal muscle

DOI:  https://doi.org/10.1002/adbi.202400091
Biomaterials. 2024 Apr 12. pii: S0142-9612(24)00102-9. [Epub ahead of print]308 122568

Optical controlled and nuclear targeted CECR2 competitor to downregulate CSF-1 for metastatic breast cancer immunotherapy.

Yi Cen, Ying Chen, Xinxuan Li, Xiayun Chen, Baixue Yu, Mengyi Yan, Ni Yan, Hong Cheng, Shiying Li.

  The crosstalk between breast cancer cells and tumor associated macrophages (TAMs) greatly contributes to tumor progression and immunosuppression. In this work, cat eye syndrome chromosome region candidate 2 (CECR2) is identified to overexpress in breast cancer patients, which can recognize v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) and activate nuclear factor κB (NF-κB) to release colony stimulating factor-1 (CSF-1). Pharmacological inhibition of CECR2 by the bromodomain competitor (Bromosporine, Bro) can downregulate CSF-1 to inhibit M2 type TAMs. To amplify the immunotherapeutic effect, a chimeric peptide-based and optical controlled CECR2 competitor (designated as N-PB) is constructed to enhance the nuclear targeted delivery of Bro and initiate an immunogenic cell death (ICD). In vivo results indicate a favorable breast cancer targeting ability and primary tumor suppression effect of N-PB under optical irradiation. Importantly, N-PB downregulates CSF-1 by competitive inhibition of CECR2 and NF-κB(RelA) interactions, thus inhibiting immunosuppressive M2-like TAMs while improving the antitumorigenic M1-like phenotype. Ultimately, the systemic anti-tumor immunity is activated to suppress the metastatic breast cancer in an optical controlled manner. This study provides a promising therapeutic target and reliable strategy for metastatic breast cancer treatment by interrupting immunosuppressive crosstalk between tumor cells and macrophages.

Keywords:  Cat eye syndrome chromosome region candidate 2 (CECR2); Colony stimulating factor-1 (CSF-1); Immunotherapy; Macrophage; Nuclear targeted delivery

DOI:  https://doi.org/10.1016/j.biomaterials.2024.122568
NPJ Syst Biol Appl. 2024 Apr 18. 10(1): 42

Characterizing heterogeneous single-cell dose responses computationally and experimentally using threshold inhibition surfaces and dose-titration assays.

Patrick C Kinnunen, Brock A Humphries, Gary D Luker, Kathryn E Luker, Jennifer J Linderman.

Single cancer cells within a tumor exhibit variable levels of resistance to drugs, ultimately leading to treatment failures. While tumor heterogeneity is recognized as a major obstacle to cancer therapy, standard dose-response measurements for the potency of targeted kinase inhibitors aggregate populations of cells, obscuring intercellular variations in responses. In this work, we develop an analytical and experimental framework to quantify and model dose responses of individual cancer cells to drugs. We first explore the connection between population and single-cell dose responses using a computational model, revealing that multiple heterogeneous populations can yield nearly identical population dose responses. We demonstrate that a single-cell analysis method, which we term a threshold inhibition surface, can differentiate among these populations. To demonstrate the applicability of this method, we develop a dose-titration assay to measure dose responses in single cells. We apply this assay to breast cancer cells responding to phosphatidylinositol-3-kinase inhibition (PI3Ki), using clinically relevant PI3Kis on breast cancer cell lines expressing fluorescent biosensors for kinase activity. We demonstrate that MCF-7 breast cancer cells exhibit heterogeneous dose responses with some cells requiring over ten-fold higher concentrations than the population average to achieve inhibition. Our work reimagines dose-response relationships for cancer drugs in an emerging paradigm of single-cell tumor heterogeneity.

DOI: https://doi.org/10.1038/s41540-024-00369-x
Cancer Res. 2024 Apr 18.

Omental preadipocytes stimulate matrix remodeling and IGF signaling to support ovarian cancer metastasis.

Jennifer A Waters, Mikella Robinson, Omar Lujano-Olazaba, Cassidy Lucht, Samuel F Gilbert, Carrie D House.

Ovarian cancer can metastasize to the omentum, which is associated with a complex tumor microenvironment. Omental stromal cells facilitate ovarian cancer colonization by secreting cytokines and growth factors. Improved understanding of the tumor supportive functions of specific cell populations in the omentum could identify strategies to prevent and treat ovarian cancer metastasis. Here, we showed that omental preadipocytes enhance the tumor initiation capacity of ovarian cancer cells. Secreted factors from preadipocytes supported cancer cell viability during nutrient and isolation stress and enabled prolonged proliferation. Co-culturing with pre-adipocytes led to upregulation of genes involved in extracellular matrix (ECM) organization, cellular response to stress, and regulation of insulin-like growth factor (IGF) signaling in ovarian cancer cells. IGF-1 induced ECM genes and increased alternative NF-κB signaling by activating RelB. Inhibiting the IGF-1 receptor (IGF1R) initially increased tumor omental adhesion but decreased growth of established preadipocyte-induced subcutaneous tumors as well as established intraperitoneal tumors. Together, this study shows that omental preadipocytes support ovarian cancer progression, which has implications for targeting metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2613
Cell Death Dis. 2024 Apr 18. 15(4): 279

Cancer-associated fibroblasts secrete FGF5 to inhibit ferroptosis to decrease cisplatin sensitivity in nasopharyngeal carcinoma through binding to FGFR2.

Feng Liu, Ling Tang, Huai Liu, Yanzhu Chen, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Pan Chen.

Cisplatin (DDP)-based chemoradiotherapy is one of the standard treatments for nasopharyngeal carcinoma (NPC). However, the sensitivity and side effects of DDP to patients remain major obstacles for NPC treatment. This research aimed to study DDP sensitivity regulated by cancer-associated fibroblasts (CAFs) through modulating ferroptosis. We demonstrated that DDP triggered ferroptosis in NPC cells, and it inhibited tumor growth via inducing ferroptosis in xenograft model. CAFs secreted high level of FGF5, thus inhibiting DDP-induced ferroptosis in NPC cells. Mechanistically, FGF5 secreted by CAFs directly bound to FGFR2 in NPC cells, leading to the activation of Keap1/Nrf2/HO-1 signaling. Rescued experiments indicated that FGFR2 overexpression inhibited DDP-induced ferroptosis, and CAFs protected against DDP-induced ferroptosis via FGF5/FGFR2 axis in NPC cells. In vivo data further showed the protective effects of FGF5 on DDP-triggered ferroptosis in NPC xenograft model. In conclusion, CAFs inhibited ferroptosis to decrease DDP sensitivity in NPC through secreting FGF5 and activating downstream FGFR2/Nrf2 signaling. The therapeutic strategy targeting FGF5/FGFR2 axis from CAFs might augment DDP sensitivity, thus decreasing the side effects of DDP in NPC treatment.

DOI: https://doi.org/10.1038/s41419-024-06671-0
Mol Cell Biochem. 2024 Apr 15.

Crosstalk between lipid metabolism and EMT: emerging mechanisms and cancer therapy.

Zaheer Ud Din, Bai Cui, Cenxin Wang, Xiaoyu Zhang, Arshad Mehmood, Fei Peng, Quentin Liu.

  Lipids are the key component of all membranes composed of a variety of molecules that transduce intracellular signaling and provide energy to the cells in the absence of nutrients. Alteration in lipid metabolism is a major factor for cancer heterogeneity and a newly identified cancer hallmark. Reprogramming of lipid metabolism affects the diverse cancer phenotypes, especially epithelial-mesenchymal transition (EMT). EMT activation is considered to be an essential step for tumor metastasis, which exhibits a crucial role in the biological processes including development, wound healing, and stem cell maintenance, and has been widely reported to contribute pathologically to cancer progression. Altered lipid metabolism triggers EMT and activates multiple EMT-associated oncogenic pathways. Although the role of lipid metabolism-induced EMT in tumorigenesis is an attractive field of research, there are still significant gaps in understanding the underlying mechanisms and the precise contributions of this interplay. Further study is needed to clarify the specific molecular mechanisms driving the crosstalk between lipid metabolism and EMT, as well as to determine the potential therapeutic implications. The increased dependency of tumor cells on lipid metabolism represents a novel therapeutic target, and targeting altered lipid metabolism holds promise as a strategy to suppress EMT and ultimately inhibit metastasis.

Keywords:  Cancer; Cancer stem cell; Cancer therapy; Epithelial–mesenchymal transition (EMT); Lipid metabolism

DOI:  https://doi.org/10.1007/s11010-024-04995-1
Adv Sci (Weinh). 2024 Apr 19. e2309298

M2 Tumor-Associated Macrophages-Derived Exosomal MALAT1 Promotes Glycolysis and Gastric Cancer Progression.

Yanzheng Wang, Jiahui Zhang, Hui Shi, Maoye Wang, Dan Yu, Min Fu, Yu Qian, Xiaoxin Zhang, Runbi Ji, Shouyu Wang, Jianmei Gu, Xu Zhang.

  M2-polarized tumor-associated macrophages (M2 TAMs) promote cancer progression. Exosomes mediate cellular communication in the tumor microenvironment (TME). However, the roles of exosomes from M2 TAMs in gastric cancer progression are unclear. Herein, it is reported that M2 TAMs-derived exosomes induced aerobic glycolysis in gastric cancer cells and enhanced their proliferation, metastasis, and chemoresistance in a glycolysis-dependent manner. It is identified that MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is enriched in M2 TAM exosomes and confirmed that MALAT1 transfer from M2 TAMs to gastric cancer cells via exosomes mediates this effect. Mechanistically, MALAT1 interacted with the δ-catenin protein and suppressed its ubiquitination and degradation by β-TRCP. In addition, MALAT1 upregulated HIF-1α expression by acting as a sponge for miR-217-5p. The activation of β-catenin and HIF-1α signaling pathways by M2 TAM exosomes collectively led to enhanced aerobic glycolysis in gastric cancer cells. Finally, a dual-targeted inhibition of MALAT1 in both gastric cancer cells and macrophages by exosome-mediated delivery of siRNA remarkably suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Taken together, these results suggest that M2 TAMs-derived exosomes promote gastric cancer progression via MALAT1-mediated regulation of glycolysis. The findings offer a potential target for gastric cancer therapy.

Keywords:  MALAT1; exosomes; gastric cancer; glycolysis; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/advs.202309298