Knockdown of CRB2 reduces the level of H4K20me2 by enhancing LSD1 expression

Luminal breast cancer is rising rapidly among East Asian women, particularly younger patients, with variable clinical outcome, yet current risk-stratification models inadequately predict early recurrence of under-studied young-onset cases. We hypothesize that the interplay between endogenous mutagenic processes and overlooked environmental carcinogen exposure drives molecular diversity, revealing novel etiologic and therapeutic insights. We performed integrative proteogenomic profiling of 164 prospective, treatment-naïve early-stage Taiwanese breast cancer patients using whole-exome sequencing, transcriptomics, proteomics, and phosphoproteomics. Functional validation in luminal models confirmed therapeutic vulnerabilities and biomarkers, with an independent cohort (n = 270) used to stratify high-risk recurrence patients. Our integrative proteogenomic analysis revealed distinct molecular etiologies and actionable vulnerabilities. For the first time, mutation signature analysis revealed both environmental carcinogen exposure (DBAC) and endogenous APOBEC mutagenesis as key contributors to poor disease-free survival, particularly in younger patients. A high-mutation-burden, immune-evasive subgroup revealed immunoepigenetic vulnerabilities. DBAC-driven tumors exhibited overexpression of ROS-detoxifying enzymes, DNA-damage checkpoint activation, and suppressed DNA repair pathways, supporting an environmental–genomic cooperative mechanism. APOBEC-associated tumors exhibited upregulation of APOBEC3B/3F/3G, steroid hormone biosynthesis enzymes, and downstream oncogenic signaling, forming an immunotherapy-responsive subtype. Proteomic classification further resolved luminal heterogeneity beyond PAM50, identifying two clinically relevant groups: (1) a young DBAC-proteome subset with suppressed DNA-repair machinery and favorable chemotherapy response; and (2) a recurrence-prone subtype characterized by co-activating ER, PI3K–AKT–mTOR, and CDK4/6/9 signaling. Functional validation demonstrated that selective CDK9 inhibition targeting the p-POLR2A-Ser2 axis significantly outperformed CDK4/6 blockade. Furthermore, a companion panel (HDAC2, ALDH1L2, ARF4, SCAMP3) stratified high-risk recurrence patients in an independent cohort, supporting biomarker-guided therapy for aggressive luminal breast cancer. This study uncovers environmental mutagenesis as a previously overlooked but critical driver of luminal breast cancer heterogeneity in East Asian patients. We establish a proteogenomics-transformative scheme to guide risk stratification and subtype-specific vulnerabilities, offering a precision oncology strategy for early-stage East Asian breast cancer management.

Malignant pleural effusion burdens quality of life and often recurs after pleurodesis because sclerosants distribute unevenly and interact variably with mesothelium. Here, we report an ultrasound-responsive liquid-foam of microbubbles designed to coat pleural surfaces broadly and to transiently enhance cellular permeability via sonoporation. Foam formulations were characterized for size, stability, ultrasound-mediated cavitation in vitro and in an orthotopic mouse model. Insonation of drug-loaded foam increased drug penetration with dependencies on exposure duration and acoustic pressure. Aligning bubble size with ultrasound frequency improved sonoporation efficiency. In vivo, tigecycline-laden foam combined with extracorporeal ultrasound induced broad tissue adhesion and fibrosis across pleural surfaces, accompanied by elevated fibrogenic signaling, consistent with successful pleurodesis and superior to solution or gel formulations. Quantification of pleurodesis endpoints combined histology with deep-learning image analysis to measure coverage, adhesion uniformity, and fibrosis across lung lobes, indicating robust and durable treatment effects and a practical path toward clinical deployment. This approach provides a clinically accessible strategy to improve pleurodesis and establishes a generalizable platform for ultrasound-guided delivery of therapeutic agents into body cavities.

WTX.AP peptide demonstrates potent antitumor activity in both in vitro and in vivo models

CRB2 competitively inhibits the binding of USP7 to LSD1

Supplementary Figure S1 shows that BRCA1 deficiency promotes GPX4i–induced ferroptosis. Supplementary Figure S2 shows that BRCA1 regulates GPX4 through the BRCT domain. Supplementary Figure S3 shows that BRCA1 deficiency suppresses erastin-induced ferroptosis via interference with VDAC3 transcription and mitochondrial lipid peroxidation.Supplementary Figure S4 shows that PARPi synergize with GPX4i in BRCA1-deficient cancers via ferroptosis. Supplementary Figure S5 shows that PARPi combined with GPX4i in BRCA1-mutant/deficient or homologous-recombination-restored cells or tumors. Supplementary Figure S6 shows that NCOA4-mediated ferritinophagy coupled with defective GPX4 induction contributes to the synergy of PARPi and GPX4i in BRCA1-deficient cancer cells. Supplementary Figure S7 shows that GPX4i overcome resistance to PARPi in BRCA1-mutant tumors.

H4K20me2 ChIP-seq-differentially genes in LSD1(E8A)-overexpressing vs. NC Fadu cells

Video footage obtained from a blue-light activation experiment using a 488-nm laser to stimulate WTX-CCD2.mCherry.Cry2

Twenty ferroptosis-related differential genes were identified by sequencing

Clinicopathological parameters in 114 patients with HNSCC

Epidermal growth factor receptor (EGFR) activation contributes to pancreatic cancer etiology, yet anti-EGFR therapy offers minimal clinical benefits in patients with KRAS mutations. We report that plasminogen activator inhibitor-1 (PAI-1) derived from cancer-associated fibroblasts (CAFs) is selectively elevated in KRAS-mutant tumors and functions as a ligand of EGFR, contributing to resistance to anti-EGFR therapy. Ablation of stromal PAI-1 breaks the CAF-tumor interaction, curbing tumor growth and enhancing the therapeutic efficacy of anti-EGFR therapy in both genetically engineered mouse models and patient-derived xenografts. Mechanistically, KRAS mutation in PDAC activates c-Myc to release IL-1α from PDAC cells to stimulate NF-κB signaling in CAFs to turn on the transcription of PAI-1. PDAC patients with KRAS mutations have higher plasma PAI-1 levels than those with wild-type KRAS. Our findings reveal a mechanism through which CAFs and tumor cells are regulated by the interaction between PAI-1 secreted by CAFs and EGFR on tumor cells. Importantly, the newly identified ligand-receptor interaction of PAI-1-EGFR in the tumor microenvironment of pancreatic cancer may open a new avenue for understanding receptor biology.

H4K20me2 ChIP-seq-differentially genes in CRB2-overexpressing vs. NC Fadu cells

Nuclear paraspeckles play critical roles in orchestrating gene transcription to support tumor development and progression. Elucidating regulators of their dynamic compositions and formation could provide potential targets for treating cancer. In this study, we discovered that the short isoform of Wilms tumor gene on the X chromosome (WTX-S) specifically disrupted paraspeckle stability. WTX-S selectively interacted with and sequestered NONO (also as p54nrb) from paraspeckles. Mechanistically, interaction between WTX-S and NONO induced formation of nuclear bodies via liquid-liquid phase separation (WTX-NB). The coiled-coil domain 2 directly interacted with NONO-coiled-coil domain to compartmentalize paraspeckle proteins and subsequently disrupt paraspeckle stability. Functionally, the paraspeckle disintegration induced by WTX-NBs resulted in enhanced chemotherapy sensitivity and favorable prognosis in gastric cancer. Importantly, the cell-penetrating synthetic peptide WTXAP, based on the WTX-NONO interface, mimicked WTX-NB-mediated paraspeckle disintegration and exhibited potent antitumor activity. Likewise, treatment with KPT-330, an FDA-approved XPO1 inhibitor, significantly increased the extent of WTX-S-mediated paraspeckle disintegration, sensitizing WTXhigh gastric cancer to chemotherapy. Collectively, these findings characterize the function and potential clinical significance of WTX-NBs, offering a strategy for sensitizing gastric cancer to chemotherapy.Significance: WTX binding to NONO regulates the balance of biomolecular condensates, providing an axis that can be harnessed to perturb paraspeckles and improve chemotherapy sensitivity in gastric cancer.

Abstract Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and remains difficult to treat due to the absence of targeted therapies. While recent advances in immunotherapy, particularly with immune checkpoint inhibitors (ICIs), have transformed the treatment landscape for many cancers, response rates to ICIs remain low for TNBC, largely due to tumor-intrinsic immune evasion mechanisms. Objective: We identify and characterize a novel immune evasion pathway in TNBC driven by deregulation of cancer cell-intrinsic protease-activated receptor 1 (PAR1), a thrombin receptor frequently upregulated in aggressive tumors. Methods and Results: Through integrative bioinformatic analyses, genetic perturbations, xenograft models (immunodeficient and immunocompetent), flow cytometry-based tumor immune profiling, and RNA-seq, we demonstrate that PAR1 activation enhances immune evasion in TNBC. Mechanistically, we show that the paracaspase MALT1 acts as a critical downstream effector of PAR1 signaling and promotes immune escape by driving PD-L1 expression in TNBC cells. Functional assays reveal that genetic depletion of MALT1 or PD-L1 increases TNBC cell susceptibility to T cell-mediated cytotoxicity in vitro and significantly suppresses tumor growth in vivo. Notably, through knock-in and rescue experiments using a catalytically inactive MALT1 mutant, we reveal that MALT1’s scaffolding - rather than protease - function is essential for PD-L1 regulation. Immune cell depletion assays further identify CD4+ T cells, CD8+ T cells, and natural killer (NK) cells as key mediators of the anti-tumor immune response suppressed by the PAR1-MALT1 axis. These findings are supported by human TNBC specimen analyses, where MALT1 expression inversely correlates with T cell activation and positively associates with PD-L1 in PAR1-high, but not PAR1-low, tumors. Conclusion: Our study reveals immune evasion as a novel mechanism of PAR1-driven breast cancer pathogenesis, mediated by a PAR1/MALT1/PD-L1 signaling cascade. These findings bridge a critical gap by positioning MALT1 at the interface between tumor-intrinsic signaling and the immune microenvironment - two areas of CARMA-BCL10-MALT1 (CBM) complex research that have largely evolved in parallel over the years. Importantly, targeting MALT1 may enhance immunotherapy efficacy in TNBC. Given the availability of MALT1 inhibitors in clinical development, our work supports combining MALT1 inhibition with ICIs or other immune-oncology agents as a promising strategy to overcome immune resistance in TNBC. Citation Format: Dong Hu, Prasanna Ekambaram, Zheqi Li, Linda Klei, Maria L. Beecher, Yi Liu, Zongyou Cai, John Little, Jeffrey A. Meridew, Jia-Ying Lee, E. Aubrey Thompson, Tullia C. Bruno, Lidija Covic, Seung-Oe Lim, Anushka Dongre, Heide L. Ford, Mien-Chie Hung, Adrian V. Lee, Steffi Oesterreich, Linda McAllister-Lucas, Peter C. Lucas. A cancer cell-intrinsic PAR1/MALT1/PD-L1 signaling pathway drives immune evasion in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7392.

Identification of protein-CRB2 interactions based on LC-MS/MS

Correlation table of CRB2, SLC7A11 and H4K20me2

Supplementary materials and methods, Supplementary Figures and figure legends, Supplementary Tables

Bioinformatics identifies potential epigenetic genes associated with ferroptosis in HNSCC

Cancer therapy is often constrained by targeting single pathogenic mechanisms without addressing the complex tumor microenvironment (TME). Here, we introduce FINAL (Fucoidan-docetaxel Immunomodulatory Nanoparticles as an Antitumoral Lancer), a surface-engineered nanoplatform that simultaneously targets P-selectin-expressing cancer cells and tumor-associated macrophages (TAMs). Beyond targeting specificity, fucoidan surface modification provides intrinsic bioactivities that individually modulate both cell types while coordinately reshaping the TME. FINAL achieves dual-cell orchestration through P-selectin-mediated targeting, activating both receptor-dependent signaling pathways and receptor-independent bioactivities of fucoidan and DTX. P-selectin-mediated targeting enhances cellular uptake and disrupts tumor-TAM adhesion, reducing the level of circulating hybrid cell (CHC) formation. Independent of targeting, fucoidan's bioactivity reduces cellular reactive oxygen species in cancer cells, promotes M1 macrophage polarization, and suppresses VEGF-A-mediated angiogenesis. RNA-seq transcriptomic profiling demonstrated that FINAL drives synergistic immune activation pathways while simultaneously repressing tumor progression signatures, providing mechanistic evidence for concurrent tumor-immune dynamics at the molecular level. In triple-negative breast cancer (TNBC) models, this system-level approach achieved breakthrough therapeutic outcomes, including doubling survival duration, suppressing primary tumor growth, inhibiting lung metastasis, and preserving bone marrow hematopoietic function, demonstrating translational potential compared to conventional docetaxel formulations. Importantly, FINAL maintained therapeutic benefits while reducing systemic toxicity, establishing an optimal balance between antitumor efficacy and safety. The rationally designed fucoidan nanobio interface establishes FINAL as a versatile platform for P-selectin-expressing diseases for next-generation immunochemotherapy agents with broad translational potential across multiple cancer types.

Adenosine deaminase acting on RNA 1 (ADAR1) contributes to immunotherapy resistance by suppressing interferon signaling. Therapeutic targeting of ADAR1 has not been achieved to date in clinical settings. Here, we discover all-trans retinoic acid (ATRA) promotes ADAR1 protein degradation in cancer. In addition, ATRA induces PD-L1 and combination of ATRA and PD-1 blockade reprograms tumor microenvironments to unleash antitumor immunity, thereby impeding tumor growth. Mechanistically, we identify USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts USP7-ADAR1 interaction and promotes ADAR1 ubiquitination and degradation. ATRA leads to ADAR1 retinoylation, which results in disruption of USP7-ADAR1 complex. Our clinical data shows a positive correlation between USP7 and ADAR1 in various types of cancer. Overall, this study sheds light on control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically "cold" into "hot" tumors, holding potential for clinical translation.