ABSTRACT Advanced prostate cancer metastasizes primarily to bone, a process driven in part by the de novo expression of bone‐associated factors (osteomimicry) that enables tumor cells to colonize and thrive in the skeletal environment. During the early stages of tumorigenesis in multiple cancer types, the primary cilium, a non‐motile microtubule‐based sensory organelle, is lost. However, the causes of primary cilium loss and the consequences of this process for tumor progression are still ill‐defined. The aim of this study was to determine whether MINDIN, a protein secreted by prostate tumor cells, promotes primary cilium reduction and osteomimicry, thereby enhancing the ability of prostate cancer cells to colonize bone. We observed that upregulation of MINDIN decreased the levels of the primary cilia marker Ift88 in association with the overexpression of Pth1r , Pthlh , and other osteomimicry‐related genes in an in vivo mouse pre‐metastatic prostate cancer model. Stimulation with MINDIN decreased primary cilia presence and length and promoted tumor cell osteomimicry, proliferation, and migration; processes similarly induced in primary cilia‐inhibited adenocarcinoma prostate cells. Ablation of Pth1r inhibited the effects of both MINDIN and primary cilium loss on prostate cancer cell osteomimicry, proliferation, and migration. Furthermore, Pth1r overexpression and Ift88 downregulation were associated with enhanced tumor cell growth in an ex vivo bone mouse model. Collectively, these findings indicate that MINDIN induces primary cilia attenuation leading to activation of PTH1R, thereby driving osteomimicry and facilitating prostate cancer cell colonization of bone.
ABSTRACT NIMA‐related kinase 2 (NEK2) is a cell cycle regulator aberrantly overexpressed in multiple cancers, yet its non‐mitotic roles in oral squamous cell carcinoma (OSCC) invasion and metastasis remain unclear. Here, we analyzed public transcriptomic and single‐cell datasets and found that NEK2 is significantly upregulated in OSCC tissues, with higher expression in cases exhibiting lymph node metastasis and associations with poor prognosis. Functional assays demonstrated that NEK2 promotes OSCC cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). Transcriptomic and pathway analyses revealed that NEK2 activates TNF‐α inflammatory signaling, and rescue experiments confirmed that the pro‐invasive effects of NEK2 are largely dependent on TNF‐α pathway activation. Through immunoprecipitation–mass spectrometry, we identified three core desmosomal proteins—desmoplakin (DSP), desmoglein‐1 (DSG1), and junction plakoglobin (JUP)—as novel NEK2‐interacting partners. NEK2 binding impaired desmosomal adhesion function at cell–cell junctions, and DSP overexpression partially rescued NEK2‐induced TNF‐α secretion, EMT, and invasion. In vivo, NEK2 knockdown suppressed xenograft tumor growth, preserved junctional desmosomal protein localization, and downregulated TNF‐α target genes. Collectively, our findings uncover a NEK2–desmosome–TNF‐α signaling axis that drives OSCC invasion and metastasis, providing new mechanistic insights and highlighting NEK2 as a potential therapeutic target.
ABSTRACT Traditional fermented products of the Indian Himalayas are gaining attention due to their health benefits. Ladakh hard chhurpi (LHC) collected from different altitudes (2784–4523 m) was assessed for antioxidant and ACE inhibitory activities. The activity of LHC generally increased upon GI digestion. Peptidome analysis of GI‐digested LHCs revealed varying peptide profiles and the presence of bioactive and multifunctional peptides. Comparative peptidome analysis of Ladakh (Western Himalaya) and Sikkim (Eastern Himalaya) cheese revealed 5 common peptides. Amino acid composition analysis revealed proline and leucine to be the most abundant in Ladakh and Sikkim cheese, respectively. The MPO and ACE inhibitory potential of several novel peptides were predicted. VYPFPGPI demonstrated high MPO binding affinity. GGVSLPE was predicted to have the best ACE inhibition potential. In vitro activity assessment revealed VYPFPGPI as a more potent ACE inhibitor (IC 50 of 215.5 ± 7.87 μM), while GGVSLPE showed higher MPO inhibitory activity (IC 50 of 0.84 ± 0.05 mM) between the two peptides. This is the first report on the LHC peptidome profile and comparative peptidome analysis of the hard cheese of Ladakh and Sikkim. The present study proposes bioactive peptides‐enriched LHCs as a functional food of Ladakh with nutraceutical potential.
ABSTRACT Oral squamous cell carcinoma (OSCC) develops through a continuum of tissue states from chronic inflammation and potentially malignant lesions to invasive cancer, yet the dynamic remodeling of the oral immune microenvironment and its relevance to immunotherapy‐associated inflammation remain poorly understood. Here, we integrated single‐cell RNA sequencing, spatial transcriptomics, murine immunotherapy datasets, and experimental validation to characterize immune and stromal alterations across healthy mucosa, periodontitis, leukoplakia, and OSCC. This integrated analysis revealed distinct oral immune microenvironment states and identified condition‐associated neutrophil programs, including an S100A12‐enriched inflammatory state, an S100A14‐associated metabolic state in leukoplakia, and tumor‐associated neutrophil states in OSCC. Spatial analyses and cell–cell communication modeling further nominated immune–stromal interaction networks involving S100A12 + neutrophils and fibroblast‐associated inflammatory signaling. A machine‐learning framework identified a nine‐gene Neu_S100A12‐associated signature that discriminated periodontitis‐associated inflammatory states across two retrospective cohorts, with seven concordantly upregulated genes prioritized for biological validation. Multiplex immunofluorescence and an IFN‐γ‐primed OSCC inflammatory model provided experimental support for a TNF‐associated inflammatory phenotype linked to the S100A12 program. Together, these findings establish a cross‐sectional multi‐omics framework for defining oral immune states and identify S100A12‐associated neutrophil programs as candidate mediators of oral inflammation and immunotherapy‐related immune perturbation, providing a foundation for future prospective and mechanistic studies.
ABSTRACT Marine‐derived collagen (MDC) represents a sustainable source of bioactive biomolecules derived from marine processing by‐products, with emerging applications in molecular nutrition and healthy aging. Compared with mammalian collagen, MDC exhibits distinctive structural characteristics, including variable imino acid composition, reduced thermal stability, and enhanced enzymatic accessibility, which determine its physicochemical properties, processing behavior, and biological potential. These structural features also underpin the distinct functional roles of native collagen and collagen‐derived peptides: intact MDC retains triple‐helical architectures and extracellular matrix‐interactive motifs that support cellular responses and tissue homeostasis, whereas hydrolyzed marine collagen peptides (MCPs) are orally administered bioactive peptides that can undergo gastrointestinal absorption and have been investigated for potential systemic health effects. This review summarizes current advances in the molecular characteristics, sustainable production, structural modification, and biological functions of MDC and MCPs, emphasizing the structure–function relationships that govern their nutritional and physiological effects. We discuss how extraction and processing strategies regulate collagen architecture, peptide generation, and bioactivity, and further examine the molecular mechanisms that have been proposed to underlie the antioxidant, anti‐inflammatory, metabolic regulatory, and musculoskeletal protective effects of MCPs. Particular attention is given to aging‐associated physiological decline, in which oxidative stress, chronic inflammation, and extracellular matrix deterioration contribute to impaired tissue homeostasis. Emerging experimental evidence suggests that marine collagen‐derived bioactive peptides may modulate key signaling pathways, including Nrf2‐mediated antioxidant responses, NF‐κB‐related inflammatory regulation, and pathways involved in connective tissue remodeling and metabolic balance. Finally, we highlight current challenges limiting the broader application of MDC‐derived biofactors, including source variability, structural and compositional standardization, bioavailability characterization, and the need for well‐designed human studies. By integrating marine sustainability, molecular structure, and biological function, MDC and its derived peptides may serve as promising food‐derived biofactors with potential applications in supporting healthy aging and age‐related health maintenance.
