Aug 2026· Cells· Vol 15, pp. 1532· 0 citations· 40 references
TL;DR
It is demonstrated that PDCD10 loss promotes GBM neo-angiogenesis involving complementary paracrine and GSC-like plasticity mechanisms, highlighting PDCD10 as a potential therapeutic target to suppress neo-angiogenesis in GBM.
Abstract
Glioblastoma (GBM) is characterized by extensive neo-angiogenesis, which drives rapid tumor growth and therapeutic resistance. We previously identified PDCD10 as a tumor suppressor in GBM. Here, we investigated whether PDCD10 loss promotes neo-angiogenesis through paracrine signaling and GBM cell plasticity. PDCD10 knockdown (shPDCD10) enhanced endothelial angiogenic activity after treatment with conditioned medium (CM) from shPDCD10 cells and in a direct co-culture model. Moreover, application of CM to the chicken chorioallantoic membrane increased vascular branching in an in vivo angiogenesis model. Antibody array analysis detected elevated levels of multiple pro-angiogenic factors following PDCD10 depletion. In a GBM mouse model, shPDCD10 tumors exhibited pronounced hypervascularity and stromal expansion. Indeed, immunofluorescence revealed colocalization of CD31 with the tumor cell reporter RFP in a subset of implanted shPDCD10 GBM cells, suggesting that these tumor cells acquired an endothelial molecular signature. PDCD10 loss also promoted a glioma stem cell (GSC)-like phenotype, characterized by enhanced clonogenicity, sphere formation, and upregulation of Nestin, KLF4, and SOX2. Under endothelial induction conditions, shPDCD10 sphere-derived cells exhibited endothelial-like characters, showing greater tube-forming capacity and increased Ac-LDL uptake. Taken together, these findings demonstrate that PDCD10 loss promotes GBM neo-angiogenesis involving complementary paracrine and GSC-like plasticity mechanisms, highlighting PDCD10 as a potential therapeutic target to suppress neo-angiogenesis in GBM.
Glioblastoma (GBM) is the most aggressive primary brain tumor, and is characterized by rapid growth, therapeutic resistance, and a highly immunosuppressive tumor microenvironment (TME). Progranulin (GRN/PGRN), a secreted glycoprotein, promotes malignancy in various cancers, yet its role in GBM remains poorly defined. Bioinformatics analysis of GEO (Gene Expression Omnibus) and TCGA (The Cancer Genome Atlas) datasets revealed that GRN expression is significantly upregulated in GBM and is associated with shorter overall survival and progression-free survival. High GRN levels correlated strongly with increased M2 macrophage infiltration (marked by CD163 expression) and elevated immune and stromal scores, suggesting that GRN contributes to an immunosuppressive TME. In vitro, silencing GRN in GBM cells markedly inhibited cell proliferation, migration, invasion, and colony formation. Coculture assays demonstrated that GRN knockdown reduced GBM-induced M2 macrophage polarization (CD206+) while increasing M1 polarization (CD86+), accompanied by decreased secretion of the immunosuppressive cytokines IL-10 and TGF-β. Transwell experiments further showed that GRN promoted GBM invasion in a macrophage-dependent manner via the TGF-β pathway, an effect that was abrogated by the TGF-β receptor I inhibitor LY3200882. We developed SORT1-loaded hyaluronic acid methacrylate (HAMA) hydrogel microspheres to target GRN therapeutically. SORT1 competitively binds to GRN, reducing its concentration in the TME. Intratumoral injection of these microspheres significantly suppressed GBM xenograft growth in vivo. Collectively, our findings identify GRN as a key driver of GBM progression and TME immunosuppression through M2 macrophage polarization and TGF-β signaling. Targeting GRN with SORT1-loaded HAMA microspheres represents a promising adjuvant therapeutic strategy for GBM.
He Zhang, Shuai Yuan, Yawen Pan· American journal of translat...· 0 citations
Immunosuppressive tumor microenvironment is a major driver of tumor progression and therapeutic resistance. Basal-like breast cancer (BLBC), which largely overlaps with triple-negative breast cancer, generally displays an immunosuppressive tumor microenvironment enriched with tumor-associated macrophages and other immunosuppressive cell populations. However, the driving mechanisms that establish and maintain these tumor microenvironment features remain not fully understood. This study identifies tumor cell-intrinsic POU4F1 as a key regulator of the immunosuppressive tumor microenvironment in BLBC. Tumors with high POU4F1 expression exhibited lower IFNγ-related signature and poor responses to immunotherapy. In immunocompetent 4T1 tumor-bearing mice, POU4F1 knockout led to decreased infiltration of M2-like macrophages and increased infiltration of proliferative and functional CD8+ T cells and NK cells. In-vitro assays using human immune cells demonstrated that POU4F1 directly promoted monocyte recruitment and macrophage polarization, which in turn suppressed the proliferation and effector function of tumor-specific CD8+ T cells and NK cells. Mechanistically, POU4F1 upregulated CCL2 expression through NIK-mediated activation of the non-canonical NF-κB signaling pathway, thereby promoting monocyte recruitment and immunosuppressive phenotype polarization. Genetic ablation or pharmacological targeting of POU4F1 with Bobcat339 significantly inhibited tumor growth, remodeled the tumor immune microenvironment, and synergized with anti-PD-1 therapy in mouse models and patient-derived breast cancer organoids. These findings provide mechanistic insights into how POU4F1, a BLBC-specific transcription factor, orchestrates intercellular crosstalk to establish an immunosuppressive, tumor-supportive microenvironment, and indicate that targeting POU4F1 may represent a promising therapeutic strategy for BLBCs.
Jiahui Zhang, Nanyan Miao, Yunzhi Guo et al.· Cancer Letters· 0 citations
Glioblastoma multiforme (GBM), a highly aggressive primary brain malignancy, is characterized by its accelerated development, refractoriness to therapy, and dismal prognosis. The proteasome subunit β2 (PSMB2), a catalytic unit of the 20S proteasome, has been linked to tumorigenesis across multiple malignancies; however, its signaling and therapeutic relevance in GBM remains incompletely defined. U87 and U251 GBM cells were engineered to overexpress (OE-PSMB2) or silence (Sh-PSMB2) PSMB2. We assessed the function of PSMB2 in GBM cell proliferation, migration, and related phenotypes, and further examined its association with the PTEN/PI3K/AKT signaling axis at both transcriptomic and protein levels. A xenograft model was conducted in the intracranial setting where the therapeutic efficacy of PSMB2 silencing, when used together with temozolomide (TMZ), was assessed. PSMB2 overexpression stimulated GBM cell proliferation, migration, and invasion, and PSMB2 silencing inhibited these phenotypes and promoted apoptosis. RNA-seq showed that PI3K/AKT pathway was enriched in Sh-PSMB2 cells. Protein-level analysis showed that PSMB2 expression was inversely associated with PTEN abundance and was accompanied by altered PI3K/AKT pathway activity. PSMB2 silencing decreased tumor burden and increased survival in vivo, and the combination of PSMB2 silencing and TMZ produced the greatest therapeutic effect. PSMB2 may function as a tumor-promoting regulator in GBM and is associated with PTEN/PI3K/AKT pathway modulation. Targeting PSMB2 suppressed tumor progression and enhanced the therapeutic response to TMZ in vivo, suggesting that PSMB2 may represent a potential therapeutic target for GBM.
Here, we report the identification of a previously unrecognized population of tumor-induced podoplanin-positive (PDPN+) cells in clear-cell renal cell carcinoma (ccRCC) that exhibit features of under-differentiated lymphatic endothelial cells (LECs). These PDPN+ cells lack a complete repertoire of canonical LEC markers, including VE-cadherin, LYVE1, and VEGFR3, and fail to form functional lymphatic vessels, indicating a dysplastic phenotype. We termed these cells dysLECs and found that these cells are induced by BMP10 produced specifically by tumor cells. In turn, dysLECs secrete CXCL13, which promotes tumor cell proliferation and metastasis. Ligand-receptor analyses revealed a highly tumor-specific reciprocal signaling circuit: kidney tubule cells deficient in the von Hippel-Lindau (VHL) tumor suppressor gene uniquely express BMP10, a TGF-β family cytokine, whereas its receptor ALK1 is restricted to dysLECs; conversely, dysLECs produce CXCL13, while VHL mutant kidney tubule cells uniquely express its receptor, CXCR5. Pharmacological inhibition of ALK1 reduced CXCL13 production and suppressed the hyperplastic phenotype of VHL mutant tumor cells in vivo, whereas BMP10 neutralization inhibited tumor growth and metastasis in an orthotopic ccRCC xenograft model. Collectively, these findings identify a dysplastic population of PDPN+ lymphatic-like endothelial cells and define a tumor-specific BMP10-CXCL13 signaling axis that drives ccRCC progression, uncovering a previously unrecognized therapeutic vulnerability in this disease.
Tuong-Vi Nguyen, Hieu-Huy Nguyen-Tran, Thi-Ngoc Nguyen et al.· International Journal of Mol...· 0 citations
Hypoxia-activated endothelial cells drive NSCLC aggressiveness and VM through a paracrine axis involving ITPR3-mediated ER calcium activation, and this HIF-1α/ITPR3 axis represents a potential therapeutic target for disrupting the tumor-vascular niche in NSCLC.
Wenhao Ji, Shizhou Yang, Xiaojing Lai et al.· Biochemical Pharmacology· 0 citations
A GSTT1HighCD133High stem-like subpopulation in metastatic PDA is identified and an FGFR-dependent signaling axis that sustains this state is identified, representing a potential therapeutic vulnerability.
D. de la Caridad Delgado Herrera, Alejandro Arroyo Roman, Riyan N. Campbell et al.· Cancer Letters· 0 citations