NPJ Precision Oncology最新文献

Compressive stresses are linked to the malignancy state of tumors. These stresses can drive cancer cells toward a malignant phenotype. The objective of this study is to investigate how patient-specific heterogeneity of a tumor tissue influences the stresses experienced by tissue components that are believed to play important roles in malignancy state. A unique image-based, physics-driven in silico modeling is developed, replicating a breast tumor tissue with the complexity and heterogeneity as observed in humans. This model employes images acquired by Fourier transform infrared (FTIR) microscopy which images and classifies breast tissues into six components including non-cancerous, malignant, others, dense, loose, and reactive stroma. We show that heterogeneous tissues having small and disconnected pieces of malignant components experience higher stresses, highlighting the dependency of stress magnitude on components' configuration, neighborhood, and initial surface area. Our in silico model predicts stresses on pre-cancerous lesions in the range that drive them to become lethal.

Sex differences in cancer susceptibility and prognosis are partially driven by sex chromosomes and sex hormones. However, the molecular mechanisms underlying the higher incidence and mortality of multiple myeloma (MM) in males remain poorly defined. In this study, we identify the Y-linked gene EIF1AY as a tumor-suppressive regulator in male MM. Clinical analysis reveals that partial deletions of EIF1AY in male MM patients are significantly associated with disease progression, reduced treatment responsiveness, and shorter overall survival. Functionally, loss of EIF1AY promotes M2 macrophage polarization and recruitment, thereby enhancing MM cell proliferation. Mechanistically, EIF1AY forms a protein complex with RPS4Y1 that directly binds to and stabilizes CD134 mRNA, thereby promoting CD134 expression in MM cells. The RPS4Y1-EIF1AY-CD134 axis suppresses IL-4 and IL-13 secretion from MM cells, which in turn downregulates the membrane receptor DDR1 on co-cultured macrophages, thereby inhibiting M2 macrophage polarization and recruitment, and ultimately restraining MM cell proliferation. These findings uncover a feed-forward loop in which the RPS4Y1-EIF1AY-CD134 axis suppresses IL-4/IL-13-DDR1 signaling, thereby suppressing M2 macrophage polarization and recruitment, and sustaining tumor growth through reciprocal crosstalk between tumor cells and macrophages. Collectively, our study elucidates a novel immune regulatory pathway driving sex differences in MM and highlights EIF1AY as a promising target for precision immunotherapy in male patients.

Anaplastic large cell lymphoma (ALCL) is a rare form of mature T cell lymphoma in children, particularly the anaplastic large cell kinase (ALK) negative subtype. Despite frontline treatment advances, there is no standard approach to treat relapsed disease and prognosis remains poor. Recently, JAK/STAT activating mutations have been implicated in the pathogenesis of ALK-negative ALCL in adults, but the oncogenic drivers of this disease in children are not well characterized. Herein, we describe a case of a 13 year-old boy with early systemic relapse of ALK-negative ALCL harboring a rare ATXN2L::JAK2 fusion, who achieved complete remission with ruxolitinib monotherapy. Consolidative allogeneic hematopoietic stem cell transplant HSCT then lead to long-term remission. This case underscores the critical role of comprehensive genomic profiling for rare histologies and supports the potential utility of JAK/STAT pathway inhibitors in select patients with ALK-negative ALCL.

Artificial intelligence (AI) is being used in oncological drug development to address the high costs, low success rates, and long timelines that characterize traditional drug development pipelines. The use of machine learning (ML) and deep learning (DL) models in computer-aided drug design is constantly growing owing to their capacity to analyze large, heterogeneous datasets, their ability to capture nonlinear biological trends, and their integration of various molecular and clinical characteristics. AI applications accelerate target discovery by predicting protein structures, ranking disease-relevant genes, and assessing target drugability. AI can be used to conduct rapid searches of multiplexed chemical libraries, predict drug-target interactions, and optimize the pharmacological and physicochemical properties of drugs in virtual screening. Advanced neural network designs also aid in de novo drug design, which involves developing new molecular structures with therapeutic properties of interest. This review outlines how AI has been used for target identification, virtual screening, de novo molecular design, and, specifically, in cancer applications. It further discusses the major issues in AI-based drug development, such as data quality, model interpretation, computational constraints, and ethical and regulatory considerations, which remain essential obstacles to broader clinical translation.

Hepatocellular carcinoma (HCC) remains a major global health challenge due to its molecular heterogeneity, late diagnosis, and limited therapeutic options. Recent studies have identified isonicotinylation (K_inic), a novel lysine acylation, as a regulatory modification influencing carcinogenic protein activity and liver cancer progression. In this study, we established the K_inic Index (K_inicI), an artificial intelligence (AI)-driven predictive model that integrates multi-omics data and consensus clustering to classify HCC patients into two distinct K_inic subgroups. Patients in the high-K_inic subgroup exhibited significantly worse overall survival, demonstrating the value of K_inicI for risk stratification and outcome prediction. Machine learning approaches (LASSO, RSF) coupled with Shapley additive explanation (SHAP) analysis identified CYP2C9 and G6PD as the most influential prognostic variables associated with HCC progression. Single-cell and spatial transcriptomic analyses confirmed that CYP2C9 and G6PD are primarily localized in malignant hepatocytes with high metastatic potential, underscoring their clinical relevance. Importantly, using the GraphBAN deep learning framework and ADMET-AI screening, we prioritized candidate compounds targeting CYP2C9 and G6PD, followed by molecular docking that validated strong binding affinities, suggesting their potential as novel therapeutics. Together, our study demonstrates that K_inicI is a powerful AI-enabled platform for prognostic modeling, molecular stratification, and multitarget drug discovery, providing a foundation for precision oncology and resistance-aware treatment strategies in HCC patients.

Immunotherapy has significantly improved the treatment of metastatic solid tumors; however, detecting early signs of response to enable timely intervention for resistant tumors remains challenging. A blood-only circulating tumor DNA (ctDNA) test may provide a rapid assessment of tumor response without reliance on matched tumor tissue. We applied a tissue-agnostic, genome-wide methylation enrichment assay, based on cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq), to plasma samples from patients in a phase 2 trial evaluating pembrolizumab across multiple solid tumors (NCT02644369). A decrease in ctDNA from baseline to pre-cycle 3 was significantly associated with higher objective response and clinical benefit rates and longer progression-free and overall survival in univariate analyses, with these associations remaining significant in multivariable models except for overall survival. These results validate a commercial-grade, tissue-agnostic plasma cfDNA methylation platform for immunotherapy response monitoring, which may facilitate earlier, more informed treatment decisions and improve patient outcomes.

Proteins are ultimately responsible for cellular phenotypes and are targeted by most anticancer drugs. However, beyond immunohistochemistry, proteins are not typically measured in precision oncology, meaning transcriptomics is used as a proxy. To determine how informative mRNA is for guiding personalised treatments, mRNA-protein correlations were analysed in three large pan-cancer datasets and made available in a web portal (https://oncorr.aws.procan.org.au/). OnCorr can be integrated into precision medicine programs to augment transcriptomics.

DEAD-box helicase 41 (DDX41) functions as an oncogene in multiple cancers and is associated with immune response. However, the specific role of DDX41 in oral squamous cell carcinoma (OSCC) has not yet been elucidated. The data from public databases show that DDX41 protein expression is elevated in OSCC tumor tissues and linked to poor prognosis. Loss of DDX41 in OSCC cells leads to an inhibition in the ability of tumor proliferation and invasion. Mechanistically, DDX41 undergoes liquid-liquid phase separation with STING, forming biomolecular condensates that potentiate PD-L1 upregulation through the STING-TBK1-NF-κB pathway. And, blocking DDX41 in the OSCC mouse model confirmed that inhibition of DDX41 decreased PD-L1-mediated immune escape via the STING-TBK1-NF-kB pathway. Flow cytometry analysis revealed significantly improved tumor immune infiltration upon DDX41 knockdown, as evidenced by altered immune cell populations. Finally, clinical sample analysis revealed that DDX41 expression is associated with poor prognosis in OSCC patients and correlates with downstream proteins. Our results identify a novel mechanism by which DDX41, functioning as a cytosolic DNA sensor, promotes PD-L1-mediated tumor immune escape in OSCC via sustaining the STING-TBK1-NF-κB signaling pathway, providing both a potential therapeutic target and diagnostic indicator for this malignancy.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide, arises from diverse etiologies that shape the tumor immune landscape, including the composition and function of innate lymphoid cells (ILCs). In this study, we integrated scRNA-seq, bulk RNA-seq, and CyTOF to profile ILCs from tumor and adjacent non-tumor liver tissues of 50 HCC patients with different etiologies (hepatitis B viral, HBV and non-viral, NV). ScRNA-seq revealed heterogenous ILC and NK clusters in non-tumor and tumor tissues. Notably, ILC1 could be subdivided into proliferative (ILC1p) and cytotoxic (ILC1c) phenotypes. ILC2 displayed classic type-2 immune traits with phenotypic heterogeneity, while ILC3 expressed key transcription factors and IL18. ILC subsets diverged significantly by disease etiology. In NV-HCC, ILC2s exhibited a pro-fibrotic and tumor-promoting signature with elevated IL13, TGFB1, and AREG expression. ILC1s in NV-HCC showed activated and cytotoxic phenotypes, whereas in HBV-HCC, they showed signs of exhaustion with increased CD96 and TIGIT. ILC1 from NV-HCC also displayed enhanced IL-2/IL-15 signaling and interactions with CD8 + T cells via HLA-E, suggestive of potential antitumor crosstalk. While our single-cell cohort size was limited, necessitating validation in larger datasets, our study reveals etiology-associated differences in ILC phenotypes in HCC and provides insight into their potential roles in modulating immune responses within the tumor microenvironment.

5-hydroxymethylcytosine (5-hmC) is a marker of open chromatin and active gene expression. We profiled 5-hmC using plasma-derived cell-free DNA (cfDNA) from patients with osteosarcoma to assess its utility as a biomarker of disease status. Genes with differential 5-hmC levels were identified from a Discovery cohort consisting of patients with osteosarcoma and healthy children. An independent Validation cohort was evaluated using these signature genes. Hierarchical clustering using 262 osteosarcoma signature genes identified in the Discovery cohort identified two clusters of samples in the Validation cohort. Cluster 1 contained 10 of 12 samples from patients with primary disease or osseous metastases, whereas Cluster 2 contained 26 of 33 samples from patients without active disease. Using a semi-quantitative osteosarcoma signature scoring system, the sensitivity and specificity to classify patients with active disease were 65% and 64%, respectively. This technique is feasible in this population, and further investigation with larger patient cohorts is warranted.