bims-stacyt 2025-05-04 papers

Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2427073122

A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity.

Liyang Zhang, Jingxuan Yang, Zhijun Zhou, Yu Ren, Bo Chen, Anliu Tang, Kailiang Zhang, Chuntao Li, Hongshu Zhou, Kar-Ming Fung, Chao Xu, Chunsheng Kang, James D Battiste, Michael S Bronze, Courtney W Houchen, Zhixiong Liu, Ian F Dunn, Webster K Cavenee, Min Li.

Glioblastoma (GBM) is the most aggressive form of brain cancer, with limited therapeutic options. While microglia contribute to GBM progression, the mechanisms by which they foster a protumorigenic immune environment remain poorly understood. We identify the zinc transporter Zrt- And Irt-Like Protein 4 (ZIP4) as a pivotal regulator of the GBM immune landscape. In orthotopic mouse models, ZIP4 drives tumor growth and behavioral changes. Mechanistically, ZIP4 modulates microglial plasticity through tumor-derived extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), a process regulated by the zinc-dependent transcription factor Zinc Finger E-box Binding Homeobox 1 in GBM cells. TREM1 enhances microglial plasticity through the spleen associated tyrosine kinase-Pyruvate dehydrogenase kinase-signal transducer and activator of transcription 3 (SYK-PDK-STAT3) signaling axis, ultimately promoting an immune environment favorable to tumor progression. ZIP4 depletion or TREM1 inhibition attenuates tumor growth and behavioral effects in vivo by disrupting the tumor-microglia interaction. These findings establish ZIP4 as a key modulator of the GBM immune landscape and suggest a promising therapeutic target to counteract microglia-mediated tumor progression.

Keywords: TREM1; exosome; glioblastoma; microglia

DOI: https://doi.org/10.1073/pnas.2427073122

Biochim Biophys Acta Mol Basis Dis. 2025 Apr 23. pii: S0925-4439(25)00216-9. [Epub ahead of print]1871(6): 167868

GDF15 drives de novo lipogenesis and contributes to ovarian cancer metastasis.

Chenxi Wang, Zhengjie Ou, Hongming Deng, Ying Zhang, Xiaoyang Li, Xiaobing Wang, Dan Zhao.

Ovarian cancer is frequently diagnosed at an advanced stage, characterized by extensive metastasis. Recent studies indicate that metastatic and primary tumors exhibit similar mutational landscape, suggesting that non-mutational factors significantly contribute to the metastatic process. Enhanced lipid metabolism has been implicated across various stages of cancer progression, making the targeting of metabolic vulnerabilities a promising therapeutic strategy. In this study, we demonstrate that growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, which has been Indicated to be associated with several metabolic diseases, is significantly elevated in the serum of ovarian cancer patients, particularly in metastatic lesions compared to primary tumors. Elevated GDF15 levels correlate with reduced overall survival and progression-free survival. Furthermore, we found that GDF15 facilitates tumor metastasis by regulating de novo lipogenesis through the PI3K/AKT signaling pathway. These findings suggest that targeting GDF15-mediated lipid metabolism could provide a novel therapeutic approach to inhibit ovarian cancer metastasis.

Keywords: GDF15; Lipogenesis; Ovarian cancer metastasis; PI3K/AKT pathway

DOI: https://doi.org/10.1016/j.bbadis.2025.167868

Biochem Biophys Res Commun. 2025 Apr 23. pii: S0006-291X(25)00601-1. [Epub ahead of print]766 151887

Glucose deprivation induces cisplatin resistance through upregulation of SLC7A11 (xCT) expression in endometrial cancer cells.

Kohei Aoyama, Kaori Yoriki, Kota Aoki, Ayaka Okamura, Yosuke Tarumi, Hisashi Kataoka, Tetsuya Kokabu, Taisuke Mori.

Cisplatin resistance poses a substantial barrier to the successful treatment of advanced endometrial cancer. Glucose deprivation in the tumor microenvironment, resulting from inadequate vascularization and rapid proliferation of cancer cells, may promote chemoresistance by modifying cellular metabolism and survival pathways. This study aimed to elucidate how glucose deprivation induces cisplatin resistance in endometrial cancer cells, focusing on the role of solute carrier family 7 member 11 (SLC7A11, xCT). The endometrial cancer cell lines HEC-1A and AN3CA were cultured under glucose-deprived and glucose-supplemented conditions. Cisplatin half-maximal inhibitory concentration (IC50) values, SLC7A11 expression, and reactive oxygen species (ROS) levels were assessed using cell proliferation assays, real-time PCR, Western blotting, and fluorescence assays. SLC7A11 was inhibited using small interfering RNA (siRNA) knockdown and the selective inhibitor HG106. Cisplatin-resistant cell lines were generated to evaluate the effect of SLC7A11 inhibition. Glucose deprivation significantly decreased cisplatin sensitivity and increased cisplatin IC50 values (P < 0.05). This reduction in sensitivity was accompanied by upregulation of SLC7A11 expression and decreased ROS levels (P < 0.05). Inhibition of SLC7A11, either by siRNA or HG106, increased cisplatin sensitivity and ROS production, even in cisplatin-resistant cells (P < 0.05). This effect was reversible with the antioxidant N-acetylcysteine. These findings demonstrate that glucose deprivation induces cisplatin resistance in endometrial cancer cells by upregulating SLC7A11, leading to reduced ROS levels and enhanced cell survival. Targeting SLC7A11 restores cisplatin sensitivity by elevating ROS production, even in cisplatin-resistant cells. The findings suggest that SLC7A11 is a promising therapeutic target for overcoming chemoresistance in endometrial cancer, potentially improving treatment outcomes and patient survival.

Keywords: Chemoresistance; Endometrial cancer; Glucose deprivation; Microenvironment; Reactive oxygen species; SLC7A11 (xCT)

DOI: https://doi.org/10.1016/j.bbrc.2025.151887

Front Cell Dev Biol. 2025 ;13 1561856

Extracellular vesicles: messengers of cross-talk between gastric cancer cells and the tumor microenvironment.

Xiwen Li, Xian Lu, Mi Liu, Junjie Chen, Xirong Lu.

Gastric cancer is a common malignancy characterized by an insidious onset and high mortality rate. Exosomes, a special type of extracellular vesicle, contain various bioactive molecules and have been found to play crucial roles in maintaining normal physiological functions and homeostasis in the body. Recent research has shown that the contents of exosome play a significant role in the progression and metastasis of gastric cancer through communication and regulatory functions. These mechanisms involve promoting gastric cancer cell proliferation and drug resistance. Additionally, other cells in the gastric cancer microenvironment can regulate the progression of gastric cancer through exosomes. These include exosomes derived from fibroblasts and immune cells, which modulate gastric cancer cells. Therefore, in this review, we provide a brief overview of recent advances in the contents and occurrence mechanisms of exosome. This review specifically focused on the regulatory mechanisms of exosomes derived from gastric cancer and other cellular subtypes in the tumor microenvironment. Subsequently, we summarize the latest research progress on the use of exosomes in liquid biopsy, discussing the potential of gastric cancer exosomes in clinical applications.

Keywords: exosome; gastric cancer; interaction; regulation; tumor microenvironment

DOI: https://doi.org/10.3389/fcell.2025.1561856

Nat Commun. 2025 May 02. 16(1): 4112

LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.

The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.

DOI: https://doi.org/10.1038/s41467-025-58753-y