Redirecting glucose into the pentose phosphate pathway (PPP) is a strategy used by cancer cells to facilitate accelerated proliferation and dissemination. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of PPP. However, the regulation of G6PD in hepatocellular carcinoma (HCC) has not been well understood. Here we found that G6PD activity was induced in HCC tissues. G6PD inhibition, by its inhibitor 6-aminonicotinamide (6-AN) or siRNA, attenuated HCC metastasis. CAPS1 (calcium-dependent activator protein for secretion 1) was identified as a novel regulator of G6PD. CAPS1 C2 domain directly interacted with the N-terminus of G6PD. This interaction disrupted G6PD dimer formation and inhibited G6PD activity. In HCC, CAPS1 down-regulation, primarily due to miR-30d-5p elevation, accumulated metabolic products in PPP. Loss of CAPS1 elevated ROS level, an event that induced epithelial-mesenchymal transition (EMT) process and HCC metastasis via ERK and GSK3β signals. Importantly, these effects could be reversed in vitro and in vivo by G6PD inhibitors, 6-AN, or siRNA. Our studies revealed CAPS1 as a novel regulator of G6PD and suggested that G6PD inhibition, such as 6-AN, represented a strategy for HCC therapy in patients with low CAPS1 expression.

Intratumoral heterogeneity contributes to therapy resistance and immune evasion in breast cancer, making treatment strategies more complex. This study integrates single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq deconvolution to characterize tumor subpopulations and develop a robust prognostic model.

It has been extensively studied that IFN-I inhibits tumor progression through their intrinsic functions in tumor cells, of which, regulating tumor cell immunogenicity is a critical way. Besides to tumor cells, myeloid cells also comprise a major component of tumor microenvironment. Nevertheless, whether IFN-I modulates the immunogenicity and function of myeloid cells in tumor microenvironment is less explored. In this research, we report that IFNβ effectively induces Ly6C myeloid cell differentiation in vitro in mouse. In human PBMCs, CD14CD33 monocytic population was consistently accumulated in the presence of IFNβ. In agreement, overexpression of IFNβ in tumor microenvironment by IFNBCOL01 treatment resulted in dramatic increase of tumor-infiltrating Ly6C myeloid cells and obvious tumor growth control in vivo. Of note, overexpression of IFNβ promotes the immunogenic Ly6CCD103CD11c subset accumulation in tumor-infiltrating myeloid cells. At the molecular level, we illustrated that the pSTAT1 directly binds to the irf1 promoter and that IRF1 directly binds to the Ly6C promoter in myeloid cells both in vitro and in vivo. Furthermore, anti-Ly6C blockade therapy significantly reversed the anti-tumor effect of IFNBCOL01 by restoring NOS2 expression and consequently suppressing T cell functions in tumor-bearing mice. Overall, our findings determine that IFNβ drives myeloid cells to differentiate into Ly6C subset via the stimulation of pSTAT1-IRF1 axis in myeloid cells. In addition, IFNβ inhibits the immunosuppressive enzyme NOS2 expression in Ly6C myeloid cells, which may decrease the potential immunosuppressive function of NOS2 to boost the T cell function to repress tumor, thus proposing a new perspective for the anti-tumor mechanism of IFN-I.

Promiscuous activation of growth factor receptors drives sustained MAP kinase signaling, which reinforces oncogene addiction in HPV-negative head and neck squamous cell carcinoma (HNSCC). This feature promotes invasive growth, complicating surgical resection and contributing to high rates of local relapse and poor patient outcomes. Current treatment strategies for locally advanced or non-resectable tumors targeting single growth factor receptors offer limited therapeutic benefit, underscoring the need for alternative targets. Using patient-derived tumor organoid (PDO) models of invasive HNSCC, we demonstrate that FER, a non-receptor tyrosine kinase that correlates with poor survival in HNSCC patients, is essential for growth factor receptor dependent invasive growth in Collagen-I extracellular matrix (ECM) networks. In this setting, FER promotes phosphorylation of EGFR-Y1068 and MET-Y1234/5. Additionally, FER controls ligand-dependent endocytic transport velocity, demonstrating a multifactorial regulation of proximal GFR activation during HNSCC invasion. Finally, genetic loss of function experiments or a FER-specific PROteolysis-TArgeting Chimera (PROTAC) strategy in PDO-based xenograft mouse models, demonstrate that FER is essential for invasive growth and metastasis of HNSCC. In sum, we propose that FER is an indiscriminate regulator of proximal GFR activation in HNSCC, a mechanism that may foster oncogene addition, thereby leading to invasive growth and metastasis. Based on its oncogenic roles and correlations with poor patient prognosis, we nominate FER as a potential candidate for targeted clinical intervention of HNSCC.

Previous studies have shown that the Wnt/β-catenin signaling pathway is aberrantly activated in multiple myeloma (MM) and regulates the growth of MM cells, while recent studies reported crosstalk between Wnt and STAT3 signaling in various non-MM systems. In addition, it has been shown that STAT3 regulates the expression of CD38, the key target of current antibody therapies in MM. Therefore, we aimed to investigate the impact of inhibiting the Wnt signaling on the efficacy of anti-CD38 immunotherapy.

EGF-like domain multiple-6 (EGFL6) is a secreted tumor growth/migration factor linked with poor outcomes in many tumor types. While EGFL6 is known to signal, in part, via its integrin-binding RGD domain, little else is known about EGFL6 receptors. We evaluated putative EGFL6 receptors and found that EGFL6 treatment of ovarian cancer cells leads to both transient phosphorylation of EGFR and prolonged phosphorylation of HER2 and HER3 and subsequent phosphorylation of ERK (pERK). We found that EGFL6 directly binds HER3. However, EGFL6-driven prolonged activation of HER3 is dependent on an intact EGFL6 integrin-binding RGD domain. Immunoprecipitation and proximity ligation assays confirmed that EGFL6 treatment of cancer cells induces HER2/3-integrin-β3 heterocomplexes. Suggesting EGFL6 could play a role in resistance to HER targeting therapies, EGFL6 is upregulated in EGFR/HER receptor inhibitor-resistant cells, and EGFL6 treatment increases resistance to EGFR/HER inhibitors in vitro. Interestingly, we found that, in EGFL6-treated ovarian cancer cells undergoing mitosis, pERK localizes to the centrosome. Both EGFL6-neutralizing antibodies and HER protein-targeted inhibitors resulted in aberrant pERK centrosomal localization with associated altered mitotic spindle alignment and mitotic catastrophe. Furthermore, combination anti-EGFL6 therapy with the pan-EGFR receptor inhibitor neratinib, compared to either therapy alone, led to an increase in aberrant pERK localization and cancer cell death in vitro and significant restricted tumor growth in vivo. Combined, our data suggests that EGFL6 is a new ligand for HER3 and that dual targeting of the EGFL6/HER signaling axis, via altered pERK localization, may be an effective therapeutic strategy in ovarian cancer. SIGNIFICANCE: This work reveals that EGFL6 is a previously unrecognized ligand for HER3 which can increase resistance to HER family-targeted therapy. We also reveal a novel function of pERK downstream of pHER3 at the centrosome in mitosis. Importantly, we show that EGFL6 is an important therapeutic target to enhance the efficacy of EGFR/HER-targeted therapy.

The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated cholesterol biosynthesis as a compensatory response, rendering cells sensitive to cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.

Colorectal Cancer (CRC) is the third most prevalent malignancy, leading to significant morbidity and mortality globally. Epidemiological studies suggest that chronological age and diet are among the major contributing factors correlated with the incidence of CRC. Our study aimed to provide insights into the association between age, diet, and gut microbiome in CRC using molecular techniques including RNA sequencing, cytokine analysis, and metagenomic analysis. We used syngeneic MC38 mice model divided into two age groups (old and young) and three diet groups (standard chow, calorie-restricted and high-fat). The major findings of this study are that age and diet impact intratumoral gene signaling (nuclear and mitochondrial), and hub genes we identified are associated with prognosis in CRC. Fecal microbiome analysis showed that old microbiomes have higher alpha diversity compared to young mice. Our results demonstrate that interactions between host (age) and external (diet) factors regulate tumor growth mediated by cytokines, mitochondrial derived proteins, and the gut microbiome. Collectively, our findings advance current understanding of the mechanisms by which aging, diet and gut microbiota impact CRC onset and progression though further investigation is warranted.

Cancers, especially fusion oncoprotein (FO)-driven hematological cancers and sarcomas, often develop from a low number of key mutations. Solitary Fibrous Tumor (SFT) is a rare mesenchymal tumor driven by the NAB2-STAT6 oncofusion gene. Currently, the treatment options for SFT remain limited, with anti-angiogenic drugs providing only partial responses with an average survival of two years. We constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, and we used these cells as models of SFT. High-throughput drug screens demonstrated that the BET inhibitor Mivebresib can differentially reduce proliferation in SFT cell models. Subsequently, BET inhibitors Mivebresib and BMS-986158 efficiently reduced tumor growth in an SFT patient-derived xenograft (PDX) animal model. Furthermore, our data showed that NAB2-STAT6 fusions may lead to high levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.

GM-CSF, a myeloid-priming cytokine, exhibits context-dependent effects on tumor growth and, despite its clinical use, its role in human melanoma remains undefined.

Cisplatin-based chemotherapy causes hearing loss in 40-60 % of all patients, yet effective preventative options remain limited. Building on prior animal studies, we demonstrate that oral administration of AZD5438, a potent and selective CDK2 inhibitor, provides dose-dependent protection against hearing loss in a clinically relevant multi-dose cisplatin mouse model. Protective doses (4.7 and 9.4 mg/kg b.i.d.) fall within the human-equivalent maximum tolerated dose range established in AstraZeneca trials, and exhibit plasma pharmacokinetics comparable to those in humans. Importantly, AZD5438 at 9.4 mg/kg b.i.d. does not reduce cisplatin's anti-tumor efficacy in a testicular cancer xenograft model, consistent with in vitro findings. These results support AZD5438 as a promising candidate for clinical trials to prevent cisplatin-induced hearing loss while preserving cancer treatment efficacy.

Neuroendocrine prostate cancer (NEPC) represents a highly aggressive, treatment‑refractory phenotype that frequently emerges after androgen‑deprivation therapy (ADT). Although perturbed calcium signaling has been implicated in prostate cancer bone metastasis, the specific molecular mechanisms governing NEPC progression remain incompletely characterized. Here, we delineate the MCTP1/FYN/MEF2C signaling axis as a pivotal modulator of intracellular calcium homeostasis that drives neuroendocrine differentiation (NED) and enhances tumor aggressiveness. We demonstrate that ADT upregulates MCTP1, a transmembrane protein with calcium-sensing capabilities, which subsequently activates the Src-family kinase FYN to initiate oncogenic signaling cascades. This activation induces transcriptional upregulation of bone morphogenesis-related genes, including MEF2C and ALPL. Mechanistically, calcium-responsive transcription factors ZEB1 and ZEB2 directly transactivate MEF2C, thereby integrating calcium flux with epithelial-to-mesenchymal transition (EMT) programs in prostate cancer. Elevated ZEB1/ZEB2-dependent MEF2C expression reinforces the MCTP1/FYN kinase pathway, potentiating neuroendocrine lineage commitment and ALPL enzymatic activity. Chromatin immunoprecipitation coupled with transcriptomic analyses reveals that MEF2C directly occupies regulatory elements of MCTP1, FYN, and ALPL, enabling their calcium-dependent transcriptional activation. Structure-based virtual screening identified a potent small-molecule antagonist targeting MCTP1, which markedly attenuates tumor burden, ALPL activity, and neuroendocrine marker expression in prostate cancer in vitro and in vivo models. Collectively, these findings establish MCTP1 as a novel therapeutically exploitable vulnerability in therapy-induced NEPC, providing critical insights into the calcium-dependent oncogenic signaling networks mediated by the MCTP1/FYN/MEF2C axis in advanced prostate cancer.

Extensive research has been done on the molecular mechanisms of tumor development and growth. However, multiple aspects remain elusive. We examined cellular signaling mechanisms involving platelet-derived growth factor (PDGF) and its receptor (PDGFR), using adult PDGFRα conditional knockout (α-KO) mice implanted with Lewis lung carcinoma (LLC) cells, which express PDGFRα. Unexpectedly, α-KO mice exhibited larger tumors and extensive lung metastasis compared to control mice. Mechanistically, under the activation of PDGF-BB-PDGFRα signal axis in LLC cells, transforming growth factor-α (TGF-α) induced accelerated tumor growth via epidermal growth factor receptor (EGFR) signal. Insufficient vascular development with lower pericyte coverage was also noted, leading to hypoxia and increased expression of transforming growth factor-β (TGF-β), which induced as a critical signaling molecule determining lung metastatic changes with the AKT1 activity. Our findings suggested that PDGFRα in interstitial cells may serve a protective role against tumor progression and selective inhibition of PDGFRα in tumor cells could offer a more targeted therapeutic approach for cancer patients. Statement of significance: PDGFRα in interstitial cells in tumors governs multiple cellular signals such as PDGF-BB, TGF-α, and TGF-β and plays a protective role in tumor progression.

Triple-negative breast cancer (TNBC) exhibits a high propensity for spinal metastasis, leading to severe morbidity and limited therapeutic responses. However, the molecular mechanisms driving spinal colonization remain poorly defined. Here, we identify the epigenetic reader ZMYND8 as a key mediator of TNBC spinal metastasis. ZMYND8 is significantly upregulated in spinal metastatic lesions and correlates with adverse patient outcomes. Transcriptomic profiling reveals that spinal metastases display profoundly immunosuppressive microenvironments, with elevated M2 macrophage infiltration positively associated with ZMYND8 expression. Mechanistically, ZMYND8 functions as a scaffold protein that promotes assembly of the DDX3X-CK1ε complex, thereby activating WNT/β-catenin signaling and promoting spinal metastasis. Furthermore, we identify OTUD4 as a bona fide deubiquitinase that directly interacts with and stabilizes ZMYND8, thereby enhancing TNBC cell migration, invasion, and spinal colonization. The resulting OTUD4-ZMYND8-DDX3X signaling axis drives canonical WNT/β-catenin signaling, upregulates CSF1 expression and promotes M2 polarization of macrophages, collectively fostering invasive behavior and establishing an immunosuppressive niche conducive to spinal metastasis. Collectively, these findings establish the OTUD4-ZMYND8-DDX3X axis as a pivotal regulator of spinal metastasis in TNBC and highlight its potential as a therapeutic target for inhibiting metastatic progression.

Androgen receptor (AR) signaling remains a key driver of castration-resistant prostate cancer (CRPC), with AR splice variants like AR-V7 contributing to resistance against second-generation antiandrogens. Targeting the AR N-terminal domain (NTD) provides a strategy to bypass ligand-binding domain (LBD)-mediated resistance. We developed ITRI-148, a CRBN-based AR-NTD degrader incorporating a rigid piperidine-alkyne linker optimized for oral pharmacokinetics. ITRI-148 efficiently degrades full-length AR, AR-V7, and clinically relevant mutants (L702H, H875Y). It facilitates the recruitment of active AR species to CRBN in the nucleus, promoting their polyubiquitination and proteasomal degradation. In CRPC and enzalutamide-resistant models, ITRI-148 robustly suppresses AR signaling and inhibits cell viability, outperforming enzalutamide. With long-term treatment, it achieves sustained AR suppression without inducing compensatory AR-V7 upregulation or PSA re-expression. In vivo, ITRI-148 demonstrates potent antitumor efficacy in both castrated and hormone-intact CRPC models, supported by favorable pharmacokinetic properties, stability and safety profiles. These findings position ITRI-148 as a promising next-generation AR-targeting agent capable of degrading resistant AR variants and providing durable inhibition of AR signaling in advanced prostate cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States and predicted to soon surpass colorectal cancer as the second. The lack of screening tests, advanced stage at diagnosis, and resistance to current treatment regimens underscore the urgent need for novel therapeutic strategies. Targeting lipid rafts, which are specialized membrane microdomains integral to cancer-related processes such as the epithelial-mesenchymal transition, angiogenesis, and metastatic dissemination, offers a promising strategy to combat this deadly disease. As these catalytic platforms regulate signal transduction pathways key to both cell survival and chemoresistance, we investigated the effects of their disruption on PDAC programmed cell death and proliferation using the dynamin inhibitor, Dynasore. In a panel of human PDAC cell lines, Dynasore reduced lipid rafts in the plasma membrane, resulting in increased oxidative and proteotoxic stress which activated the ATR-Chk1 DNA damage response and initiated programmed cell death. Caspase-1 activation led to pyroptosis in the human PDAC cell lines, BxPC-3 and MIA PaCa-2, while Caspase-3 activation induced apoptosis in MIA PaCa-2 and L3.6pl. These cell-specific cell death responses resulted in dose- and time-dependent antiproliferative effects that enhanced gemcitabine cytotoxicity. Our findings suggest that lipid raft inhibition can modulate proliferation, distinct cell death pathways, and treatment response in PDAC. Given the limitations of current therapies, these results emphasize the need for further investigation into lipid raft-targeting agents in combination with chemotherapy to overcome chemoresistance in pancreatic cancer. SIGNIFICANCE: Dynasore exerts potent anti-proliferative and synergistic effects with gemcitabine in vitro by disrupting lipid rafts and differentially inducing programmed cell death, highlighting its potential as a novel therapy in PDAC.

A comprehensive understanding of the mechanisms by which air pollutant exposure drives cancer progression remains incomplete. Particulate matter has been shown to induce genotoxicity and mutagenesis through oxidative stress both in vivo and in vitro. However, its impact on the pulmonary immune microenvironment and its role in modulating anti-tumour immune responses remains poorly characterized. Here, we report that chronic exposure to diesel exhaust particles (DEPs), a major component of PM2.5, induces an immunosuppressive lung microenvironment that promotes tumour progression in a KRAS-driven lung adenocarcinoma model (Kras-Trp53 or KP mice). This environment is characterized by the emergence of PMN-MDSC (CD14 PMNs) that exhibit NET formation and an immunosuppressive gene expression and functional profile. Additionally, we observed increased infiltration of regulatory T cells (Tregs), and upregulation of exhaustion/activation and immunosuppressive markers on T cells, factors that likely contribute to the increased tumour burden and enhanced tumour cell proliferation seen in DEP-exposed KP mice. Our study reveals how chronic DEP exposure reshapes the lung microenvironment in ways that may impair the ability to mount effective anti-tumour immune responses. These findings highlight the need for stronger public and occupational health policies aimed at reducing air pollution and its associated disease burden.

Oxaliplatin, a platinum-based anticancer drug, is commonly used to treat gastrointestinal cancers, including gastric cancer. However, resistance to platinum-based therapies often leads to poor clinical outcomes for gastric cancer patients. Overexpression and activation of FGFR4 signaling have been identified as drivers of tumorigenesis in several types of cancer, including gastric cancer. In this study, we investigated the therapeutic efficacy of combining the FGFR4 inhibitor H3B-6527 with oxaliplatin using in vitro and in vivo gastric cancer models. Using gastric cancer cell lines, cell viability and clonogenic cell survival assays revealed that the combination treatment significantly reduced cancer cell viability and colony formation, compared to either agent alone (p < 0.01). Interestingly, treatment with oxaliplatin alone increased FGFR4 expression in the resistant cancer cell population. Western blot analysis confirmed the heightened DNA damage (γH2AX, cleaved PARP) alongside suppressed pro-survival signals (phospho-STAT3 and BCL2 family). Apoptosis was markedly enhanced, as demonstrated by Caspase-3/7 and TUNEL assays (p < 0.01). In human gastric cancer-derived tumoroids, the combination therapy significantly reduced both the size and number of tumoroids. In patient-derived xenograft (PDX) models, the combined treatment approach outperformed single-agent treatments in reducing tumor growth and improving survival. Immunofluorescence and immunohistochemistry analyses of PDX tumors showed an increase in DNA damage (γH2AX) and apoptosis (cleaved caspase-3) along with a reduction in cell proliferation (KI67). These findings indicate that H3B-6527 enhances gastric cancer sensitivity to oxaliplatin by amplifying DNA damage and disrupting cell survival pathways. This study provides a rationale for clinical trials targeting FGFR4 in gastric cancer.

Filamin A (FLNA) is an actin binding protein that organizes the cytoskeleton and controls many fundamental biological processes, such as cell migration and adhesion. The interaction between FLNA and the Myocardin-related transcription factor A (MRTF-A) promotes the activity of serum response factor (SRF) and cell migration. MRTF-A and SRF play an important role for tumor growth and senescence of hepatocellular carcinoma (HCC). Here, we identified a novel interaction between FLNA and the tumor suppressor Deleted in Liver Cancer 1 (DLC1) in vitro and in vivo in organoids and mapped the regions of interaction between DLC1 and FLNA. Association with FLNA enhanced DLC1 RhoGAP function, impaired SRF transcriptional activity, and induced cellular senescence. We found a novel molecular switch between the DLC1-FLNA and the MRTF-A-FLNA complexes that is mediated by FLNA phosphorylation at serine 2152. We generated DLC1 binding peptides that dissociate the MRTF-A-FLNA complex and favor the novel DLC1-FLNA complex by preventing actin polymerization and FLNA phosphorylation at serine 2152. Since FLNA phosphorylation at serine 2152 was increased in mouse xenografts, reinforcing the DLC1-FLNA complex by targeting FLNA phosphorylation at serine 2152 represents a promising therapeutic approach for HCC treatment.