Lunquan Sun

Circadian rhythm (CR) governs systemic and tissue physiological homeostasis by regulating sleep-wake cycles, hormone secretion, and metabolism. CR disruption (CRD), such as shift work, has been associated with increased cancer risk, particularly female breast cancer (BC), yet the mechanisms underlying breast tumorigenesis and immunosuppression resulting from a specific clock gene dysfunction remain unclear. Here, we identify that circadian regulator Period 2 (PER2) is significantly downregulated in BC and correlates with poor prognosis. PER2 functional deficiency mice ( PAS-B domain deletion, Per2 ^m/m ) display high susceptibility to DMBA/MPA-induced breast tumors. Tumor microenvironment (TME) profiling reveals that compared with Per2 ^wt tumors induced in Per2 ^wt mice, Per2 ^m/m tumors generated in Per2 ^m/m mice show reduced CD8⁺ T cells and M1-like macrophages infiltration and increased Foxp3 ⁺ Tregs and M2-like macrophages. Of note, reciprocal transplantation of Per2 ^m/m and Per2 ^wt tumors into Per2 ^wt or Per2 ^m/m mouse hosts reveals that systemic PER2 functional deficiency status not only boosts tumor growth but also promotes immunosuppression in TME. Consistently, Per2 knockdown in tumor cells enhances tumor cell proliferation and immune evasion in WT hosts. Mechanistically, PER2 knockdown leads to aberrant CLOCK transactivation, which upregulates the co-expression of HER2 and CD47, thereby leading to tumor aggressive growth with limited macrophage immune checkpoint surveillance. Collectively, our findings suggest that PER2 functional deficiency-driven CLOCK-HER2/CD47 axis promotes BC susceptibility and tumor immunosuppression, which provides a potential therapeutic target to mitigate CRD-associated BC risk and aggressiveness.

Nasopharyngeal carcinoma (NPC) is a type of cancer that is prevalent in southern China. In the development of NPC, the oncogenic protein LMP1, which is encoded by EBV, plays a very important role. The Wnt pathway is abnormally activated in many types of malignant tumors. The interaction between AXIN and DVL2 is pivotal for the breakdown of the β‐catenin destruction complex and Wnt/β‐catenin pathway activation. However, the molecular mechanisms underlying this process in NPC are not well understood. In this study, we identified the transmembrane protein LMP1 as an interacting partner of DVL2, which positively regulates the Wnt/β‐catenin pathway by inhibiting the AXIN‐DVL2 interaction. LMP1 overexpression enhanced NPC cell growth, metastasis, and stemness, whereas LMP1 knockdown suppressed these abilities. Our findings reveal new oncogenic roles for LMP1 in NPC progression.

Telomeres, coated by the shelterin complex, prevent end-to-end fusions and aberrant DNA repair, yet how telomere-binding proteins coordinate chromatin remodeling during the DNA damage response remains unclear. Here we show that the telomeric protein TRF1 is phosphorylated at serine 11 (S11) in response to DNA double-strand breaks, a modification that enhances cellular resistance to DNA damage. We found that CDK2 directly mediates this phosphorylation, which triggers recruitment of the histone methyltransferase SETD5 to telomeric chromatin. SETD5-dependent deposition of H3 trimethylation at lysine 36 (H3K36me3) promotes local chromatin decompaction and enables subsequent recruitment of the phosphatase PPP4C to dephosphorylate γH2AX. Loss of TRF1 S11 phosphorylation results in persistent γH2AX foci, delayed DNA repair, and compromised telomere integrity. Our results define a CDK2-TRF1-SETD5-PPP4C signaling axis that orchestrates phosphorylation-dependent chromatin remodeling at telomeres to ensure genome maintenance during DNA damage stress.

PARP inhibitors (PARPi) selectively target cancers with homologous recombination deficiency (HRD), yet emerging evidence suggests that additional determinants beyond BRCA/HRD status modulate PARPi response. Here, by integrating unbiased proteomic profiling with systematic drug-response phenotyping across 11 ovarian cancer cell lines, we identify MAP2K6 as a previously unrecognized regulator of PARP1 activation and an important determinant of PARP inhibitor sensitivity in BRCA-wild-type ovarian cancer. MAP2K6 promotes global PARP1-mediated PARylation and enhances cellular responsiveness to the PARP inhibitor olaparib both in vitro and in vivo. Mechanistically, MAP2K6 can phosphorylate and activate HMGA1, which in turn transcriptionally upregulates NAMPT, resulting in increased intracellular NAD ⁺ levels, and sustained PARP1 activation. Genetic depletion of HMGA1 or NAMPT abolishes MAP2K6-driven PARylation and PARPi sensitization, whereas loss of MAP2K6 reduces NAD ⁺ levels, attenuates PARP1 activation, and confers resistance to PARPi. We propose that MAP2K6 promotes PARP inhibitor sensitivity by coupling metabolic control of NAD ⁺ supply to PARP1 activation, thereby potentially helping extend the therapeutic scope of PARP inhibition beyond homologous recombination-deficient ovarian cancer.

Neoantigen-based vaccines represent a promising approach in cancer immunotherapy, with the key to their effective clinical application lying in the precise identification of immunogenic neoantigens. Existing methods primarily focus on genomic variations, lacking integration of multi-omics data and essential filtering steps, which limits comprehensive assessment of immunogenicity and results in only a small subset of neoantigens capable of eliciting effective immune responses. Moreover, the complexity and poor portability further hinder the clinical applicability. To address these limitations, we developed OmniNeo, an automated multi-omics-based neoantigen discovery framework. 1) OmniNeo integrates whole-genome/exome sequencing (WGS/WES), transcriptomic, and proteomics data to simultaneously identify neoantigenic epitopes derived from SNVs/Indels, frameshift mutations, gene fusions, and non-coding region variations; 2) The pipeline incorporates a convolutional neural network-based model, OmniNeo-CNN along with multiple filtering mechanisms to quantify the immunogenicity and T-cell receptor (TCR) recognition potential of predicted neoantigen candidates through multiple features; 3) The workflow is built on nextflow, offering a one-stop, scalable, and portable solution for rapid and efficient neoantigen prediction. Finally, we demonstrated the practical application procedures of this workflow in potential tumor immunotherapy through case study analyses of liver cancer samples. The tool is freely accessible as an open-source resource via https://github.com/linfengxu/OmniNeo , https://zenodo.org/records/15340824 .

Epitranscriptomic data indicate that aberrant tRNA modifications in malignant diseases can promote tumor growth by facilitating oncogene translation. NSUN2, a 5-methylcytosine (m5C) methyltransferase of tRNA, is elevated in an array of solid cancers, including triple-negative breast cancer (TNBC). However, it remains unclear how NSUN2 drives aggressive behavior and if NSUN2 could be an effective therapeutic target for TNBC. Functional experiments, including RNA interference, lentivirus transduction, and in vivo xenograft models, were conducted to evaluate the role of NSUN2 in TNBC cell proliferation, metastasis, and chemoresistance. Ribosome sequencing (Ribo-seq), tRNA m5C bisulfite sequencing, and codon usage bias analysis were employed to explore the translational mechanisms underlying NSUN2-mediated tRNA modifications. Glycolysis assays and molecular docking were used to investigate metabolic reprogramming and protein interactions. NSUN2 was significantly upregulated in TNBC and correlated with poor patient prognosis. Mechanistically, NSUN2 mediates m5C modification of tRNAVal−CAC, enhancing the codon-frequency-dependent translation of key glycolysis-related genes, including ALDH3A2, ALDH7A1, HK1, and PFKM. Depletion of NSUN2 disrupted tRNAVal−CAC m5C modification, impairing the translation of these metabolic enzymes and suppressing glycolysis, which ultimately inhibited TNBC cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, NSUN2 overexpression conferred resistance to docetaxel, while its inhibition sensitized TNBC cells to docetaxel treatment. Clinically, elevated expression levels of NSUN2 and glycolysis-related genes were observed in docetaxel-resistant TNBC tissues, further supporting the role of NSUN2 in chemoresistance. This study identifies NSUN2 as a critical regulator of TNBC progression through tRNAVal−CAC m5C modification and codon-biased translation of glycolysis-related mRNAs. Our findings reveal a novel NSUN2–tRNAVal−CAC axis that orchestrates metabolic reprogramming and translational control in TNBC, offering a promising prognostic biomarker and therapeutic target.

Background: The heterogeneity of tumors significantly impacts on colorectal cancer (CRC) progression. However, the influence of this heterogeneity on the spatial architecture of CRC remains largely unknown. Methods: Spatial transcriptomic (ST) analysis of AOM/DSS-induced colorectal cancer (CRC), integrated with single-cell RNA sequencing, generated a comprehensive spatial atlas of CRC. Pseudotime trajectory, stemness evaluation, and cell-cell communication analyses explored how CD44⁺ tumor cells at the leading edge remodel the tumor microenvironment (TME). In vitro experiments and immunofluorescence staining of clinical samples validated pleiotrophin (PTN) signaling in promoting cancer-associated fibroblasts (CAFs) phenotypic transition and CRC progression. Results: Our findings revealed a distinctive layered ring-like structure within CRC tissues, where CD44⁺ tumor cells exhibiting high stemness were positioned at the tumor’s leading edge. Inflammatory CAFs (iCAFs)-like, myofibroblastic CAFs (myCAFs)-like cells and pro-tumorigenic neutrophils primarily located at the tumor edge, in proximity to CD44⁺ tumor cells. CD44⁺ tumor cells then triggered the phenotypic transition of CAFs into iCAF-like and myCAF-like cells through PTN signaling. Conclusions: Our results provide distinctive insights into how tumor heterogeneity reshapes the TME at the leading edge of tumor, thereby promoting CRC progression.

Disrupted cellular polarity (DCP) is a hallmark of solid cancer, the malignant disease of epithelial tissues, which occupies ~90% of all human cancers. DCP has been identified to affect not only the cancer cell’s aggressive behavior but also the migration and infiltration of immune cells, although the precise mechanism of DCP-affected tumor-immune cell interaction remains unclear. This review discusses immunosuppressive tumor microenvironments (TME) caused by DCP-driven tumor cell proliferation with DCP-impaired immune cell functions. We will revisit the fundamental roles of cell polarity (CP) proteins in sustaining mammary luminal homeostasis, epithelial transformation, and breast cancer progression. Then, the current data on CP involvement in immune cell activation, maturation, migration, and tumor infiltration are evaluated. The CP status on the immune effector cells and their targeted tumor cells are highlighted in tumor immune regulation, including the antigen presentation and the formation of immune synapses (IS). CP-regulated antigen presentation and delivery and the formation of IS between the immune cells, especially between the immune effectors and tumor cells, will be addressed. Alterations of CP on the tumor cells, infiltrated immune effector cells, or both are discussed with these aspects. We conclude that CP-mediated tumor aggressiveness coupled with DCP-impaired immune cell disability may decide the degree of immunosuppressive status and responsiveness to immune checkpoint blockade (ICB). Further elucidating the dynamics of CP- or DCP-mediated immune regulation in TME will provide more critical insights into tumor-immune cell dynamics, which is required to invent more effective approaches for cancer immunotherapy.

Tumor cells display profound changes in the metabolism of branched-chain amino acids (BCAA). However, how these changes are regulated to facilitate tumorigenesis is not yet completely understood. Here, we identified pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a BCAA-responsive protein through extensive screening using stable isotope labeling with amino acids in cell culture (SILAC). PPDPF is upregulated in cholangiocarcinoma to enhance the malignant phenotype of cholangiocarcinoma cells by activating the mTORC1 signaling pathway. Metabolic flux analysis and mechanistic studies revealed that PPDPF prevented the interaction between MCCA and MCCB, thus inhibiting leucine catabolism and activating mTORC1 signaling. Moreover, upon amino acid starvation, ariadne RBR E3 ubiquitin protein ligase 2 (ARIH2) and OTU deubiquitinase 4 (OTUD4) cooperatively regulated the stability of the PPDPF protein by modulating its ubiquitination. Additionally, monocytes/macrophage-derived IL-10 increased the BCAA content in cholangiocarcinoma cells and stabilized the PPDPF protein, even under amino acid starvation conditions. Knockout of PPDPF or restriction of leucine intake significantly inhibits the progression of cholangiocarcinoma in a mouse model. Collectively, we discovered a novel role for PPDPF in promoting the progression of cholangiocarcinoma by activating mTORC1 signaling through the inhibition of leucine catabolism. The present study suggests that targeting PPDPF or decreasing dietary leucine intake may provide a new strategy to improve the treatment efficacy of cholangiocarcinoma.