Molecular Oncology最新文献

Despite having excellent prognosis when detected early, colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Screening remains an important contributor to CRC survival, but the cost and invasiveness of traditional imaging methodologies can hinder patient compliance. A blood-based approach would be more convenient and accessible, but reliable serum markers are lacking. In this study, the peptide enteroendocrine hormone Fibroblast Growth Factor 19 (FGF19) was identified as an attractive marker for CRC through a meta-transcriptomic analysis. While its pro-tumor effects are documented, FGF19's utility as a blood serum marker for CRC is not well defined. Studies presented here show that FGF19 is constitutively expressed and secreted in 3 of 5 CRC cell lines, and secreted levels increase with seeding density. A subcutaneous CRC cell line-derived xenograft model revealed that FGF19 is detectable in serum of mice injected with FGF19-positive, but not negative, CRC cells at levels corresponding to tumor volume. Enteroendocrine effects of tumor-derived FGF19, including suppression of bile acid synthesis, are evident in liver samples via RNA sequencing and validated by RT-PCR. Notably, the hepatic response to CRC-secreted FGF19 has not been explored prior to this study even though FGF19 is a key regulator of hepatic cholesterol metabolism and bile acid homeostasis. Collectively, these findings support the clinical utility of FGF19 as a putative serum marker for CRC and provide important evidence that CRC-derived FGF19 can modulate liver physiology consistent with the enteroendocrine function of FGF19.

Peroxidasin (PXDN), an extracellular matrix (ECM)-associated peroxidase, has been implicated in cancer progression. However, its roles in melanoma biology and therapeutic sensitivity remain unclear. Here, we demonstrate that elevated PXDN expression is associated with poor prognosis and reduced survival in melanoma patients. Functional studies revealed that PXDN depletion impairs melanoma cell proliferation, disrupts the cell cycle, and reduces melanoma cell invasive capacities. Furthermore, we found that secreted PXDN modulates anti-melanoma immunity by enhancing melanoma resistance to natural killer (NK)-cell-mediated cytotoxicity. Structural modeling identified a trimeric organization of PXDN, stabilized by disulfide-linked peroxidase domains. Molecular dynamics simulations identified a previously unknown inhibitory interaction between the PXDN N-terminal leucine-rich repeat domain and the NK cell-activating receptor NKG2-D type II integral membrane protein (NKG2D). These findings uncover a redox-independent role for PXDN in promoting immune evasion and tumor progression. Overall, our study highlights PXDN as a critical regulator of melanoma cell biology and a potential therapeutic target for NK-cell-based immunotherapy in melanoma and other solid cancers.

According to the seed and soil hypothesis, the organ specificity of metastasis is not a random process and depends on multiple tumor-intrinsic and microenvironmental factors. In this study, we characterized the mutational landscape of a large cohort of human metastatic samples to investigate whether mutational trends determine metastatic dissemination. Genomic data from nine cancer types (bladder, breast, colorectal, endometrial, melanoma, non-small cell lung cancer, ovarian, pancreatic, and prostate) including 19827 patients were obtained from a pan-cancer study. When restricting the analysis to driver mutations, no robust, recurrent mutational patterns associated with metastatic locations were identified across cancer types. However, when cancer types were analyzed separately, mutational trends associated with specific metastatic locations emerged. Considering the total tumor mutational burden (TMB), central nervous system (CNS)/brain and lung metastases harbored a higher TMB than other metastatic locations. Since higher TMB in CNS/brain metastases was also associated with improved prognosis, these findings may be pivotal in refining immunotherapy strategies. Indeed, this observation was confirmed in an independent dataset including patients treated with immunotherapy. In conclusion, our findings suggest that TMB may have greater influence on metastatic organotropism than driver mutational background.

Cervical cancer is highly prevalent in India, with most cases being diagnosed at advanced stages. Despite the standard concurrent chemoradiotherapy (CCRT), 30-40% of patients' experience treatment failure, underscoring the need for improved therapeutic strategies. Understanding resistance mechanisms and identifying predictive biomarkers are crucial to improve treatment efficacy and enable personalized medicine. We conducted a comprehensive genomic and proteomic analysis to identify molecular signatures associated with CCRT. We identified recurrent mutations in phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) and histone-lysine N-methyltransferase 2D (KMT2D), with mutation signature analysis revealing a prevalent DNA dC- > dU-editing enzyme, APOBEC mutagenesis signature. Distinct genomic alterations, including epidermal growth factor receptor (EGFR) amplification and serine/threonine kinase 11 (STK11) deletion, were exclusively observed in the chemoradiation-resistant cohort. Proteomic analysis identified 73 significantly dysregulated proteins, with syntaxin-3 (STX3), SERPINB7, lipopolysaccharide-binding protein (LBP), EMILIN2, and ribosyldihydronicotinamide dehydrogenase (quinone) (NQO2) being the top five upregulated proteins. Integrative pathway analysis highlighted an active DNA repair pathway in the resistant cohort. This study presents the first proteogenomic profiling of cervical cancer in the Indian population, linking molecular alterations to CCRT response. STK11 and STX3 emerged as predictive biomarkers for poor response, whereas EGFR presents as a promising therapeutic target in the resistant group.

As the most common pediatric brain malignancy, medulloblastoma (MB) includes multiple distinct molecular subtypes characterized by clinical heterogeneity and genetic alterations. Accurate identification of MB subtypes is essential for downstream risk stratification and tailored therapeutic design. Existing MB subtyping approaches perform poorly due to limited cohorts and severe batch effects when integrating various MB data sources. To address these concerns, we propose a novel approach called RaMBat for accurate MB subtyping from diverse data sources with severe batch effects. Benchmarking tests based on 13 datasets with severe batch effects suggested that RaMBat achieved a median accuracy of 99%, significantly outperforming state-of-the-art MB subtyping approaches and conventional machine learning classifiers. RaMBat could efficiently deal with the batch effects and clearly separate subtypes of MB samples from diverse data sources. We believe RaMBat will bring direct positive impacts on downstream MB risk stratification and tailored treatment design.

Yes-associated protein (YAP) is a key oncogenic effector and a well-established driver of resistance to anticancer therapies, especially in tumors harboring KRAS mutations. Although YAP is clinically relevant, drug-development efforts that directly inhibit its activity have been limited. Here, we show that basroparib-a selective tankyrase (TNKS) inhibitor that suppresses Wnt signaling-attenuates YAP-driven oncogenic programs by stabilizing angiomotin (AMOT), an endogenous negative regulator of YAP. In colorectal cancer (CRC) cells, basroparib increased AMOT protein abundance, promoted AMOT-YAP complex formation, and enforced cytoplasmic sequestration of YAP, thereby dampening YAP-dependent transcription. Basroparib preferentially sensitized YAP-overexpressing, KRAS-mutant CRC cell lines to MEK inhibition by inhibiting YAP signaling. In MEK inhibitor-resistant CRC models, in which elevated YAP activity mediates escape, basroparib restored drug sensitivity both in vitro and in vivo. The compound also enhanced MEK inhibitor efficacy in other YAP-active tumor types, while exerting minimal effects in YAP-inactive models. Taken together, these results identify basroparib-now progressing through clinical development (Phase I, NCT04505839)-as a promising agent for dual Wnt-YAP pathway blockade and for overcoming therapeutic resistance in YAP-driven cancers.

PI3K inhibitors (PI3Ki) have shown promise in some hematological cancers, but further development has been hampered by reports of serious immune-related adverse effects. Thus, identification of effective PI3Ki lacking these adverse effects is desirable. Here, we evaluated the in vitro effects of the investigational PI3Ki roginolisib (IOA-244) and the approved PI3Ki idelalisib on immune cells and leukemic cells. Roginolisib inhibited chronic lymphocytic leukemia cell signaling and viability in a manner comparable to idelalisib. Both drugs specifically inhibited PI3K-signaling in T cells, validating their on-target effects. Both idelalisib and roginolisib reduced regulatory T-cell frequency in a concentration-dependent manner, with idelalisib demonstrating greater potency. Both inhibitors also reduced T-cell activation and proliferation, but to differing extents. However, only idelalisib induced a pronounced impairment of CD8⁺ T-cell cytotoxic function. Furthermore, idelalisib treatment promoted differentiation of conventional CD4⁺ T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors.

Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key immunosuppressive target on tumour-associated macrophages (TAMs), where it coordinates protumorigenic and anti-inflammatory functions within the tumour microenvironment (TME). Unfortunately, recent clinical evidence indicates that therapeutic TREM2 blockade has suboptimal efficacy in cancer patients. Now, Von Locquenghien et al. report that MiTE-144, a TREM2 blocking antibody fused to an IL2 variant with TME-restricted activation, demonstrates superior anticancer efficiency compared to TREM2 blockade alone in the preclinical setting. Importantly, MiTE-144 showed reduced systemic inflammation or hepatotoxicity relative to TREM2 blockade and/or 'generic' IL2 immunocytokine approaches. Detailed TME analysis of MiTE-144-treated tumours showed substantial reprogramming of the myeloid compartments, together with activation of NK/CD8⁺ T cells. While this study tackled several limitations of anti-TREM2 monotherapy, more attention is needed towards clinically relevant immunotherapy barriers in therapy-refractory tumour settings.

PIK3R1, a regulatory subunit of class IA phosphoinositide-3-kinase (PI3K), undergoes alternative splicing to generate multiple isoforms, primarily p85α and p55α. The canonical isoform p85α associates with the catalytic subunit p110α to form the active PI3K complex, which regulates key cellular functions such as growth, proliferation, survival, and metabolism. In this study, we performed a comprehensive pan-cancer analysis integrating transcriptomic, proteomic, and genomic data to investigate the expression patterns of p85α and its splicing variant, p55α, and their associations with clinical outcomes. Our findings reveal that while p85α expression is significantly reduced, p55α is elevated in tumors as compared to normal samples. These alterations are linked to poor prognosis across multiple cancer types. Notably, we observed racial disparities in expression patterns, with African American patients exhibiting more pronounced downregulation of p85α and upregulation of p55α than European Americans, potentially contributing to differential clinical outcomes. This is the first study to systematically evaluate p85α and p55α expression across diverse cancers and populations, highlighting the role of alternative splicing in PI3K pathway dysregulation and its relevance to cancer progression and health disparities.

Traditionally, cancer has been viewed largely as a disease of the cell, with extensive research centred on how mutations in driver genes trigger cellular transformation. Beyond cell-intrinsic changes, cancer unfolds as a systemic disease driven by an intricate dialogue between malignant cells and the host's organs and tissues. Modelling this multilayered phenomenon is challenging, as it requires recapitulating coordinated interactions within and across multiple organs, inside an organism that is contended with maintaining normal physiology. In recent years, Drosophila melanogaster has emerged as a powerful model for revealing fundamental mechanisms by which the tumour and host mutually interact. In this review, we highlight recent findings that unravel the intricacies of tumour-host biology using Drosophila. At the microenvironment level, we synthesise mechanistic findings on how tumour growth is modulated through interactions with neighbouring tumour subclones, nonmutated wild-type cells and the immune system. At the macroenvironment level, work in Drosophila has provided mechanistic insights into how tumourigenesis causes systemic host health degeneration and accelerates death, collectively termed paraneoplastic effects. Tumours can remotely induce systemic metabolic rewiring and cachectic tissue wasting to promote progression, while simultaneously compromising the function of several tissues, such as the renal system, blood-brain barrier, the gut and blood haemostasis. Additionally, we discuss how the microbiota and sexual dimorphism have been shown to affect the tumour-host interplay. With this review, we synthesise recent advances in Drosophila tumour-host biology and illustrate how this model illuminates cancer's systemic nature.