Drosophila melanogaster is a highly versatile model organism that has profoundly advanced our understanding of human diseases. With more than 60% of its genes having human homologs, Drosophila provides an invaluable system for modelling a wide range of pathologies, including neurodegenerative disorders, cancer, metabolic diseases, as well as cardiac and muscular conditions. This review highlights key developments in utilizing Drosophila for disease modelling, emphasizing the genetic tools that have transformed research in this field. Technologies such as the GAL4/UAS system, RNA interference (RNAi) and CRISPR-Cas9 have enabled precise genetic manipulation, with CRISPR-Cas9 allowing for the introduction of human disease mutations into orthologous Drosophila genes. These approaches have yielded critical insights into disease mechanisms, identified novel therapeutic targets and facilitated both drug screening and toxicological studies. Articles were selected based on their relevance, impact and contribution to the field, with a particular focus on studies offering innovative perspectives on disease mechanisms or therapeutic strategies. Our findings emphasize the central role of Drosophila in studying complex human diseases, underscoring its genetic similarities to humans and its effectiveness in modelling conditions such as Alzheimer's disease, Parkinson's disease and cancer. This review reaffirms Drosophila's critical role as a model organism, highlighting its potential to drive future research and therapeutic advancements.

Trifluridine/Tipiracil (FTD/TPI, TAS102) has been approved for the treatment of patients with colorectal cancer (CRC) for its promising anticancer activity enabled by its incorporation into double strands during DNA synthesis. However, the mechanisms underlying the anticancer targets of FTD/TPI remain not fully understood. Here we report our observation of the activation of ferroptosis in CRC by FTD/TPI. Mechanistically, FTD/TPI directly promotes the ubiquitination and degradation of MDM2, thereby stabilizing the p53. Nuclear accumulation of p53 subsequently downregulates SLC7A11 expression, leading to ferroptosis. Furthermore, we observed that FTD/TPI combined with sulfasalazine (SAS), a system Xc- inhibitor, works in a synergistic manner to induce ferroptosis and further inhibit the proliferation of CRC cells. Finally, we confirmed the synergistic effect of SAS and FTD/TPI on patient-derived organoids in vitro and patient-derived xenograft mouse models in vivo. Our findings are the first to reveal that FTD/TPI induces ferroptosis via the p53-SLC7A11 axis and that SAS enhances the sensitivity and therapeutic effect of FTD/TPI. These findings suggest that the synergistic effect of FTD/TPI and SAS may represent a new therapeutic strategy for patients with CRC.

The chaperonin tailless complex polypeptide 1 (TCP1) is a key subunit of chaperonin containing TCP1 (CCT) that regulates the folding and stability of proteins during cancer progression. Here, the prognostic significance of TCP1 was explored mainly in patients with hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC). We showed that TCP1 expression was significantly greater in clinically malignant tumour tissues than in normal tissues and that high TCP1 expression was associated with poor prognosis. TCP1 suppression not only decreased the proliferation and invasion of cancer cells in vitro but also inhibited tumour growth and metastasis in vivo. The underlying mechanisms were determined by ubiquitination assays and Co-IP (Co-Immunoprecipitation) experiments, and it was found that TCP1 regulated the stability of c-Myc through the RAC-alpha serine/threonine-protein kinase (AKT) /Glycogen synthase kinase 3β (GSK-3β) and extracellular regulated protein kinases (ERK) signalling pathways. Moreover, TCP1 knock-in (TCP1-KI) dramatically promoted the occurrence of diethylnitrosamine (DEN) -induced primary HCC in mice. Our results highlight the critical role of TCP1 in HCC and PDAC and reveal a novel mechanism to suppress HCC and PDAC by targeting c-Myc via the TCP1-induced promotion of the AKT/GSK-3β and ERK signalling pathways. TCP1 is able to modulate the stability of target proteins by multiple pathways, thus promoting the progression of HCC and PDAC. Our study identifies TCP1 as a prognostic novel marker and therapeutic target of HCC and PDAC.

The aim of our study was to characterize the spectrum of mutations in muscle-invasive bladder cancer (MIBC) in the Chinese population, identifying mutational features and exploring potential therapeutic targets.

We collected samples from 62 Chinese patients with MIBC. For each patient, tumor tissues or blood samples were collected and sequenced by whole exome sequencing.

Our findings revealed the most frequently mutated genes included TP53 (41%), TTN (41%), HYDIN (34%), FRG1 (33%), ZNF717 (23%), AHNAK2 (21%), MUC4 (21%), KMT2D (20%), CDC27 (18%) and IGSF3 (18%). The most frequently mutated DNA damage repair (DDR) genes were TP53 (49%), SMARCA4 (10%), ERCC2 (8%), BRAC2 (6%), HERC2 (6%), HLTF (6%), PALB2 (6%) and POLG (6%). Additionally, our analysis confirmed an association between DDR mutations and high TMB (P = .022). Significant differences in MSI were observed between smokers and nonsmokers (P = .022), drinkers and nondrinkers (P = .018). By analyzing the data of 323 white MIBC samples from TCGA database, we identified frequently mutated driver genes in both our cohort and TCGA white cohort, including TP53, KMT2D, KMT2C, and FGFR3. Our study also revealed genes with distinct mutation frequencies compared to the TCGA white cohort, including FRG1, CDC27, IGSF3, MUC16, and ARID1A.

Our study provided comprehensive insights into genomic alterations in a cohort of Chinese MIBC, which could provide potential clues for clinical applications.

Cellular senescence is a permanent cell growth arrest that occurs in response to various intrinsic and extrinsic stimuli and is associated with cellular and molecular changes. Long non-coding RNAs (lncRNAs) are key regulators of cellular senescence by affecting the expression of many important genes involved in senescence-associated pathways and processes. Here, we evaluated a panel of lncRNAs associated with senescence for their differential expression between young and senescent human dermal fibroblasts (NHDFs) and studied the effect of a known senomorphic compound, resveratrol, on the expression of lncRNAs in senescent NHDFs. As markers of senescence, we evaluated cell growth, senescence-associated (SA)-β-Gal staining, and the expression of p21, Lamin B1 and γH2AX. We found that H19 and PURPL were the most altered lncRNAs in replicative, in doxorubicin (DOXO) and ionising radiation (IR)-induced senescence models. We then investigated the function of H19 and PURPL in cell senescence by siRNA-mediated silencing in young and senescent fibroblasts, respectively. Our results showed that H19 knockdown reduced cell viability and induced cell senescence and autophagy of NHDFs through the regulation of the PI3K/AKT/mTOR pathway; conversely, PURPL silencing reversed senescence by reducing (SA)-β-Gal staining, recovering cell proliferation with an increase of S-phase cells, and reducing the p53-dependent DNA damage response. Overall, our data highlighted the role of H19 and PURPL in the senescent phenotype and suggested that these lncRNAs may have important implications in senescence-related diseases.

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA, encoding PI3Kalpha (also known as p110α)] is one of the most commonly aberrated genes in human cancers. In serous ovarian cancer, PIK3CA amplification is highly frequent but PIK3CA point mutation is rare. However, whether PIK3CA amplification and PIK3CA driver mutations have the same functional impact in the disease is unclear. Here, we report that both PIK3CA amplification and E545K mutation are tumorigenic. While the protein kinase B (AKT) signaling axis was activated in both E545K knock-in cells and PIK3CA-overexpressing cells, the mitogen-activated protein kinase 3/1 (ERK1/2) pathway was induced selectively by E545K mutation but not PIK3CA amplification. Intriguingly, AKT signaling in these PIK3CA-aberrated cells increased transcriptional coactivator YAP1 (YAP) Ser127 phosphorylation and thereby cytoplasmic YAP levels, which in turn increased cell migration through Ras-related C3 botulinum toxin substrate 1 (RAC1) activation. In addition to the altered YAP signaling, AKT upregulated N-cadherin expression, which also contributed to cell migration. Pharmacological inhibition of N-cadherin reduced cell migratory potential. Importantly, co-targeting N-cadherin and p110α/AKT caused additive reduction in cell migration in vitro and metastases formation in vivo. Together, this study reveals the molecular pathways driven by the PIK3CA aberrations and the exploitable vulnerabilities in PIK3CA-aberrated serous ovarian cancer cells.

JOURNAL/nrgr/04.03/01300535-202504000-00029/figure1/v/2024-07-06T104127Z/r/image-tiff Recent research has demonstrated the impact of physical activity on the prognosis of glioma patients, with evidence suggesting exercise may reduce mortality risks and aid neural regeneration. The role of the small ubiquitin-like modifier (SUMO) protein, especially post-exercise, in cancer progression, is gaining attention, as are the potential anti-cancer effects of SUMOylation. We used machine learning to create the exercise and SUMO-related gene signature (ESLRS). This signature shows how physical activity might help improve the outlook for low-grade glioma and other cancers. We demonstrated the prognostic and immunotherapeutic significance of ESLRS markers, specifically highlighting how murine double minute 2 (MDM2), a component of the ESLRS, can be targeted by nutlin-3. This underscores the intricate relationship between natural compounds such as nutlin-3 and immune regulation. Using comprehensive CRISPR screening, we validated the effects of specific ESLRS genes on low-grade glioma progression. We also revealed insights into the effectiveness of Nutlin-3a as a potent MDM2 inhibitor through molecular docking and dynamic simulation. Nutlin-3a inhibited glioma cell proliferation and activated the p53 pathway. Its efficacy decreased with MDM2 overexpression, and this was reversed by Nutlin-3a or exercise. Experiments using a low-grade glioma mouse model highlighted the effect of physical activity on oxidative stress and molecular pathway regulation. Notably, both physical exercise and Nutlin-3a administration improved physical function in mice bearing tumors derived from MDM2-overexpressing cells. These results suggest the potential for Nutlin-3a, an MDM2 inhibitor, with physical exercise as a therapeutic approach for glioma management. Our research also supports the use of natural products for therapy and sheds light on the interaction of exercise, natural products, and immune regulation in cancer treatment.

Migrasomes, recently discovered cellular substructures, may play a crucial role in cancer progression, treatment response, and prognosis. However, the prognostic value of migrasome-associated long non-coding RNAs (lncRNAs) in colon adenocarcinoma (COAD) remains unexplored.

RNA-seq data from 459 COAD patients, including clinical characteristics and outcome information, were obtained from The Cancer Genome Atlas. A risk model was constructed through co-expression analysis of migrasome genes and lncRNAs, followed by Cox regression and least absolute shrinkage and selection operator analysis to identify prognostic lncRNAs. Functional enrichment analyses were performed to elucidate underlying biological mechanisms. Immune landscape characterization utilized ESTIMATE, CIBERSORT, Tumor Immune Estimation Resource (TIME), and single-sample Gene Set Enrichment Analysis (ssGSEA). Drug sensitivity analysis was conducted for select therapeutic agents.

Nine prognostic lncRNAs (AC010463.3, AL590483.4, AP005264.1, ZEB1-AS1, AC104088.1, PRKAR1B-AS2, AC009315.1, SUCLG2-AS1, and AC006111.2) were identified and incorporated into a risk model. Low-risk patients demonstrated significantly improved survival outcomes. The model exhibited independent prognostic capability, with AUCs of 0.783, 0.749, and 0.713 for one-, three-, and five-year survival, respectively, in the training cohort. High-risk patients displayed reduced overall survival and elevated tumor mutation burden. Additionally, these patients showed decreased sensitivity to therapeutic agents, including Oxaliplatin, Irinotecan, and 5-Fluorouracil.

Our novel migrasome-associated lncRNA signature demonstrates robust predictive capacity for both prognosis and chemotherapeutic sensitivity in COAD, potentially facilitating personalized treatment strategies and improved patient management.

Next-generation sequencing (NGS) is increasingly utilized in oncological practice; however, only a minority of patients benefit from targeted therapy. Developing drug response prediction (DRP) models is important for the "untargetable" majority. Prior DRP models typically use whole-transcriptome and whole-exome sequencing data, which are clinically unavailable. We aim to develop a DRP model toward the repurposing of chemotherapy, requiring only information from clinical-grade NGS (cNGS) panels of restricted gene sets. Data sparsity and limited patient drug response information make this challenging. We firstly show that existing DRPs perform equally with whole-exome versus cNGS (∼300 genes) data. Drug IDentifier (DruID) is then described, a DRP model for restricted gene sets using transfer learning, variant annotations, domain-invariant representation learning, and multi-task learning. DruID outperformed state-of-the-art DRP methods on pan-cancer data and showed robust response classification on two real-world clinical datasets, representing a step toward a clinically applicable DRP tool.

Colorectal cancer (CRC) is a malignant tumor of the digestive tract that significantly impacts human health. LDL receptor-related protein 1B (LRP1B) may play a crucial role in tumorigenesis and disease progression.

We performed a comparative analysis of differential gene expression, mutation patterns, drug sensitivity, and cellular phenotypes across different subgroups with varying LRP1B expression levels. Cellular and molecular experiments were conducted to validate our findings.

Our analysis implicated LRP1B as a tumor suppressor gene. Experimental results confirmed that LRP1B expression was reduced in CRC and its knockdown was associated with poor prognosis. Molecular mechanism studies revealed that LRP1B negatively regulated the Hedgehog (Hh) signaling pathway, influencing cell cycle and apoptosis processes. Single-cell analysis showed significant differences in the infiltration of T cells, B cells, epithelial cells, and myeloid cells between high and low LRP1B expression groups. Immune cell infiltration and drug sensitivity analyses demonstrated that LRP1B plays a crucial role in immunotherapy and targeted therapy, suggesting that restoring LRP1B function could be a promising treatment strategy for CRC.

Our results indicate that LRP1B may function as a tumor suppressor factor in CRC, playing a significant role in mutation, therapy, and immune infiltration. Knockdown of LRP1B activates the Hh pathway in tumor cells, leading to the inhibition of several malignant biological behaviors.

Microbial impact on tumorigenesis of heritable cancers proximal to the gut is well-documented. Whether the microbiota influences cancers arising from inborn mutations at sites distal to the gut is undetermined. Using two models of heritable cancer, Trp53-deficient mice and Wnt1-transgenic mice, and a gnotobiotic approach, we found the microbiota to be inconsequential for tumor development. This work furthers our understanding of the degree of the microbial impact on tumor development.

The influence of the microbiome on the development of cancer is well-documented with many if not all published studies reporting either a positive or a negative impact. None of the published studies, however, presented data on the influence of the microbiome on the development of heritable cancer. We find that the microbiota has no influence on cancer development in two models of spontaneous cancers driven by germline Trp53 deficiency and constitutive Wnt1 signaling.

Studies have demonstrated that histone deacetylase 1 (HDAC1) enables cancer cells to evade killing mediated by cytotoxic T lymphocytes. However, there are no studies on the immunological aspects of HDAC1 in non-small cell lung cancer (NSCLC).

In this research, we used the Cancer Genome Atlas (TCGA) public database combined with tissue microarray (TMA) to investigate HDAC1 expression and prognosis in NSCLC. According to the median value of HDAC1 expression in the TCGA dataset, samples of patients with NSCLC were classified into high- and low-expression cohorts. Subsequently, the biological characteristics of HDAC1 in high- and low-expression cohorts in terms of signaling pathways, immune cell infiltration, immune cell function, and genomic stability were investigated to better understand the effect of HDAC1 in the tumor microenvironment (TME) of NSCLC. Additionally, we selected tissue samples with HDAC1 overexpression in TMA2 and performed immunohistochemical staining of CD8+ T cells to observe the distribution of CD8+ T cells in the tumor.

The findings revealed that overexpression of HDAC1 in NSCLC was associated with poor prognosis. Analysis of signaling pathway enrichment indicated that HDAC1 downregulated immune-related signaling pathways in NSCLC. Immune cell infiltration, immune cell function, and genomic stability analyses suggested that the TME alteration mediated by HDAC1 in the high-expression cohort was consistent with the "immune desert" phenotype. Furthermore, CD8+ T immunohistochemical staining experiments of tissue samples with HDAC1 overexpression in NSCLC revealed few CD8+ T cells distributed in the tumor parenchyma and interstitium.

Conclusively, our findings from several biological analyses revealed that HDAC1 is overexpressed in NSCLC and induces TME immunosuppression.

The efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. Transforming growth factor-beta (TGFβ) is associated with immune-poor, so-called cold tumors whereas loss of its signaling promotes DNA misrepair that could stimulate immune response.

We analyzed transcriptomic data from IMvigor210, The Cancer Genome Atlas, and Tumor Immune Syngeneic MOuse data sets to evaluate the predictive value of high βAlt, a score representing low expression of a signature consisting of TGFβ targets and high expression of genes involved in error-prone DNA repair. The immune context of βAlt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high βAlt preclinical tumor model was treated with a TGFβ inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control.

We found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high βAlt, cold mouse and human tumors that responded to ICB.

These studies indicate that loss of TGFβ signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy.

An 8-y-old, spayed female Bernese Mountain Dog was presented to a referral center for evaluation of right thoracic limb lameness and previously suspected Evans syndrome that had been poorly responsive to immunosuppressive therapy. Based on review of examination findings and laboratory data, Evans syndrome was deemed unlikely and hemophagocytic histiocytic sarcoma (HHS) was strongly suspected. On blood smear evaluation, atypical, histiocytic cells were noted, some of which exhibited siderophagia. Considering that circulating cells are not typically observed in dogs with HHS, additional diagnostic investigation was performed. Autopsy and histopathology revealed that the dog had a mixed form of HS (dendritic-cell origin HS in the lung, and HHS in the spleen, liver, and bone marrow), and immunocytochemical characterization of cultured cells derived from blood suggested that the cells were of dendritic HS origin, rather than HHS origin, as originally suspected. Whole-exome sequencing revealed genetic similarity between cell lines derived from lung tissue and blood, providing additional evidence of the relatedness of these 2 cell populations. Our case highlights the rare entity of mixed HS and typifies the inherent challenges in classifying rare, atypical, circulating neoplastic cells.

The crosstalk between immunity and cancer in the regulation of tumor growth is considered a hallmark of cancer. Antitumor immunity refers to the innate and adaptive immune responses that regulate cancer development and proliferation. Tumor immune evasion represents a major hindrance to effective anticancer treatment. Extracellular vesicles (EVs) are nano-sized and lipid-bilayer-enclosed particles that are secreted to the extracellular space by all cell types. They are critically involved in numerous biological functions including intercellular communication. Tumor-derived extracellular vesicles (TEVs) can transport a variety of cargo to modulate immune cells in the tumor microenvironment (TME). This review provides the latest update about how tumor cells evade immune surveillance by exploiting TEVs. First, the biogenesis of EVs and the cargo-sorting machinery are discussed. Second, how tumor cells modulate immune cell differentiation, activation, and function via TEVs to evade immune surveillance is illustrated. Last but not least, the novel antitumor strategies that can reverse immune escape are summarized.

Glioblastoma is the most common form of primary malignant brain tumor in adults and one of the most lethal human cancers, with high recurrence and therapy resistance. Glioblastoma cells display extensive genetic and cellular heterogeneity, which precludes a unique and common therapeutic approach. The standard of care in glioblastoma patients includes surgery followed by radiotherapy plus concomitant temozolomide. As in many other cancers, cell signaling is deeply affected due to mutations or alterations in the so-called molecular drivers. Moreover, glioblastoma cells undergo metabolic adaptations to meet the new demands in terms of energy and building blocks, with an increasing amount of evidence connecting metabolic transformation and cell signaling deregulation in this type of aggressive brain tumor. In this review, we summarize some of the most common alterations both in cell signaling and metabolism in glioblastoma, presenting an integrative discussion about how they contribute to therapy resistance. Furthermore, this review aims at providing a comprehensive overview of the state-of-the-art of therapeutic approaches and clinical trials exploiting signaling and metabolism in glioblastoma.

Signaling pathways often convergence on transcription factors and other DNA-binding proteins that regulate chromatin structure and gene expression, thereby governing a broad range of essential cellular functions. However, the repertoire of DNA-binding proteins is incompletely understood even for the best-characterized pathways. Here, we optimized a strategy for the isolation of Proteins on Chromatin (iPOC) exploiting tagged nucleoside analogs to label the DNA and capture associated proteins, thus enabling the comprehensive, sensitive, and unbiased characterization of the DNA-bound proteome. We then applied iPOC to investigate chromatome changes upon perturbation of the cancer-relevant PI3K-AKT-mTOR pathway. Our results show distinct dynamics of the DNA-bound proteome upon selective inhibition of PI3K, AKT, or mTOR, and we provide evidence how this signaling cascade regulates the DNA-bound status of SUZ12, thereby modulating H3K27me3 levels. Collectively, iPOC is a powerful approach to study the composition of the DNA-bound proteome operating downstream of signaling cascades, thereby both expanding our knowledge of the mechanism of action of the pathway and unveiling novel chromatin modulators that can potentially be targeted pharmacologically.

Human additional sex combs like (ASXL) proteins are involved in the maintenance of both transcriptional activation and repression through their ability to bind multiple chromatin regulators, including two tumor suppressors: deubiquitinase BAP1 and methyltransferase MLL4 (KMT2D). The ASXL genes are often altered in colorectal cancer (CRC), and ASXL1 is one of the four hub genes related to the pathogenesis of CRC. Here, we show that MLL4 and BAP1 interdependently target specific genomic regions and positively or negatively regulate expression of a subset of genes in the human colon carcinoma HCT116 cells. MLL4 and BAP1 colocalize on a subset of enhancers and promoters in an interdependent manner. Genomic distribution of BAP1 in CRC cells differs from that in ESCs, with substantially more BAP1 binding sites identified on enhancers and promoters in HCT116 cells. MLL4 occupancy on MLL4+ BAP1+ genomic regions depends on functional ASXLs that interact with both MLL4 and BAP1, and CRC-relevant mutations attenuate the formation of the MLL4-ASXL complex. Mutational analysis and binding assays identified CRC hot spot mutations in ASXLs. Our findings suggest that alterations in the genomic distribution of the MLL4-ASXL-BAP1 axis and CRC hot spot mutations in ASXLs perturb normal transcriptional programs and may trigger pathogenic events in colon cancer.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.

Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.

Nonstop extension or stop-loss mutations lead to the extension of a protein at its carboxyl terminus. Recently, nonstop mutations in the tumor suppressor SMAD Family Member 4 (SMAD4) have been discovered to lead to proteasomal SMAD4 degradation. However, this mutation type has not been studied in other cancer genes. Here, we explore somatic nonstop mutations in the tumor suppressor genes BRCA1 Associated Protein 1 (BAP1) and Von Hippel-Lindau (VHL) enriched in renal cell carcinoma. For BAP1, nonstop mutations generate an extremely long extension. Instead of proteasomal degradation, the extension decreases translation and depletes BAP1 messenger RNA from heavy polysomes. For VHL, the short extension leads to proteasomal degradation. Unexpectedly, the mutation alters the selection of the translational start site shifting VHL isoforms. We identify germline VHL nonstop mutations in patients leading to the early onset of severe disease manifestations. In summary, nonstop extension mutations inhibit the expression of renal tumor suppressor genes with pleiotropic effects on translation and protein stability.

The loss of functions of tumor suppressor (TS) genes plays a key role in not only tumor initiation but also tumor progression leading to poor prognosis. While therapeutic inhibition of oncogene-encoded kinases has shown clinical success, restoring TS functions remains challenging due to conceptual and technical limitations. E3 ubiquitin ligases that ubiquitinate TS proteins for accelerated degradation in cancers emerge as promising therapeutic targets. Unlike proteasomal inhibitors with a broad spectrum, inhibitors of an E3 ligase would offer superior selectivity and efficacy in enhancing expression of its substrate TS proteins as far as the TS proteins retain wild-type structures. Recent advances in developing E3 inhibitors, including MDM2 inhibitors, highlight their potential and ultimately guide the framework to establish E3 inhibition as effective strategies to treat specific types of cancers. This review explores E3 ligases that negatively regulate bona fide TS proteins, the developmental status of E3 inhibitors, and their promise and pitfalls as therapeutic agents for anti-cancer precision medicine.

The development of therapeutic drugs and vaccines requires the availability of appropriate model animals that replicate the pathogenesis of human diseases. Both native and transgenic animals can be utilized as models. The advantage of transgenic animals lies in their ability to simulate specific properties desired by researchers. However, there is often a need for the rapid production of transgenic animal models, especially in situations like a pandemic, as was evident during COVID-19. An important tool for transgenesis is the adeno-associated virus. The genome of adeno-associated virus serves as a convenient expression cassette for delivering various DNA constructs into cells, and this method has proven effective in practice. This review analyzes the features of the adeno-associated virus genome that make it an advantageous vector for transgenesis. Additionally, examples of utilizing adeno-associated viral vectors to create animal models for hereditary, oncological, and viral human diseases are provided.

The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from the bone marrow of 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands of cells to reconstruct phylogenetic trees of the major driver clones in each patient. We develop a computational framework that can infer levels of positive selection operating during preleukemic evolution from the statistical properties of these phylogenetic trees. Combining these data with 67 previously published phylogenetic trees, we find that the highly variable structures of preleukemic trees emerge naturally from a simple model of somatic evolution with pervasive positive selection typically in the range of 9%-24% per year. At these levels of positive selection, we show that the identification of early multiple-mutant clones could be used to identify individuals at risk of future AML.

Lung adenocarcinoma (LUAD) frequently precipitates a hypercoagulable state, resulting in venous thromboembolism and associated hemostatic complications. Furthermore, the coagulation cascade holds a pivotal role within the tumor microenvironment (TME) of LUAD. Utilizing unsupervised clustering of coagulation-related genes (CRG) and integrating clinical attributes, distinctions and correlations in clustering across various groups were assessed. Principal component analysis (PCA) was employed to derive the CRGscore for LUAD patients. Subsequently, a prognostic signature was established to contrast the impacts of immunological and pharmacological treatments across groups. The expression of PIK3CA, posited as a potential biomarker, was corroborated via immunohistochemistry(IHC) and Western blotting. This research delineated pronounced variances in immune signatures and prognostic categorizations among four coagulation-related subtypes, and delved into their associations with three gene cluster subtypes. A prognostic model based on coagulation-related scores was formulated for risk stratification and prognosis estimation. Disparities in immune infiltration, treatment modalities, and drug responsiveness among risk cohorts were discerned. Notably, an augmented expression of the coagulation-associated gene PIK3CA was observed in tumor samples. Coagulatory function is intimately linked with LUAD and its immune microenvironment, offering predictive potential for LUAD survival prognosis. Specifically, subgroups manifesting elevated PIK3CA expression might serve as foundational indicators for optimal treatment selection.

Genomic heterogeneity has largely been overlooked in single-cell replication timing (scRT) studies. Here, we develop MnM, an efficient machine learning-based tool that allows disentangling scRT profiles from heterogenous samples. We use single-cell copy number data to accurately perform missing value imputation, identify cell replication states, and detect genomic heterogeneity. This allows us to separate somatic copy number alterations from copy number changes resulting from DNA replication. Our methodology brings critical insights into chromosomal aberrations and highlights the ubiquitous aneuploidy process during tumorigenesis. The copy number and scRT profiles obtained by analysing >119,000 high-quality human single cells from different cell lines, patient tumours and patient-derived xenograft samples leads to a multi-sample heterogeneity-resolved scRT atlas. This atlas is an important resource for cancer research and demonstrates that scRT profiles can be used to study replication timing heterogeneity in cancer. Our findings also highlight the importance of studying cancer tissue samples to comprehensively grasp the complexities of DNA replication because cell lines, although convenient, lack dynamic environmental factors. These results facilitate future research at the interface of genomic instability and replication stress during cancer progression.

Bladder cancer (BLCA) is one of the ten most common cancers worldwide. However, the deregulation of PROS1 and its specific function in BLCA is not well understood. By combining proteomic and transcriptomic datasets, we discovered PROS1 expression was significantly reduced in BLCA tissues and revealed the clinical relevance of PROS1 with BLCA. Analysis of multiple BLCA datasets consistently showed the group with reduced PROS1 expression was linked to cancer-promoting pathways, more aggressive characteristics, and a greater chance of responding positively to immunotherapy. Next, various functional experiments were performed and the results revealed PROS1 overexpression inhibited the proliferation, cell cycle progression, migration, invasion, and angiogenesis of BLCA. In recovery trials, the AKT activator SC79 offered additional proof that PROS1 may influence BLCA cells via the AKT/GSK3β/β-catenin pathway. In conclusion, as an angiogenesis-related gene, PROS1 may play an inhibitory role in the biological functions of bladder cancer.

Members from the RAS GTPase superfamily have been closely implicated in the tumorigenesis of various human cancers. Recent sequencing analysis of lung adenocarcinoma has revealed the prevalence of alterations in the RIT1 gene that is a close RAS paralog. However, relative to RAS subfamily members KRAS, NRAS, and HRAS, our characterization of RIT1 oncogenic properties remains incomplete. Therefore, further investigation on RIT1 will facilitate future development of targeted therapies. Our bioinformatic analysis revealed that RIT1 alterations in lung cancer predicted poor survivals but differed from its RAS paralogs by showing largely amplification and mutation. Through biochemical characterization of RIT1 hotspot mutations, we propose that RIT1 alterations were associated with increased protein abundance that promoted cell growth. Transcriptomic profiling indicated that oncogenic RIT1 mutant expression influenced common tumorigenic RAS/MAPK, PI3K/AKT, and E2F1 pathways, in addition to altered NFE2L2 target expression. Importantly, RIT1 mutants markedly sensitized cells to ferroptosis induction, and RIT1 knockdown suppressed ferroptotic cell death. Lung adenocarcinoma NCI-H2110 cells containing endogenous RIT1 M90I mutation were susceptible to ferroptosis induction both in vitro and in vivo within xenograft models. Hence, our study unravels a novel aspect of RIT1 mutations in lung cancer and suggests ferroptosis induction as a potential therapeutic strategy to treat lung cancer patients carrying RIT1 mutations.

Cholangiocarcinoma (CHOL) is the second most common primary liver malignancy, characterized by high aggressiveness and heterogeneity. It is typically diagnosed at an advanced stage, leading to a poor prognosis. Although Peptidyl Proline Isomerase H (PPIH) has been implicated in various tumors, its role in CHOL remains unexplored. This study aims to investigate the diagnostic value and potential function of PPIH in CHOL.

We analyzed the expression levels, prognostic significance, and diagnostic efficiency of PPIH in CHOL using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, coupled with gene enrichment analyses. The CIBERSORT database was employed to assess the correlation between PPIH expression and immune cell infiltration in CHOL. Additionally, immunohistochemical experiments were conducted to validate PPIH expression levels in CHOL tissues and to explore its correlation with TP53 gene mutations.

Our findings indicate that overexpression of PPIH mRNA in CHOL is associated with poor prognosis, with increased PPIH protein levels observed in CHOL tissues. Furthermore, PPIH expression showed a positive correlation with TP53 mutations. PPIH demonstrated strong diagnostic value for CHOL. Moreover, PPIH may influence tumor progression through its involvement in cell cycle regulation and spliceosome pathways, and is associated with immune cell infiltration levels.

The results of this study suggest that PPIH is a potential novel biomarker with significant diagnostic value for patients with CHOL. PPIH may also play a role in modulating the immune microenvironment, contributing to poor prognosis.

Background: Tubulin alpha 1b (TUBA1B) is a key microtubule protein essential for maintaining cellular structure and function. This protein contributes significantly to cytoskeletal formation and is implicated in various diseases. Despite its fundamental roles, TUBA1B's impact on tumor prognosis and the tumor immune microenvironment across cancer types remains inadequately understood. Methods To elucidate TUBA1B's role in cancer prognosis and immune response, we conducted a comprehensive analysis, integrating data from established databases such as The Cancer Genome Atlas, Genotype Tissue Expression, Cancer Cell Lineage Encyclopedia, Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal, TIMER, and ImmuCellAI, along with a large-scale clinical study and immunotherapy cohort. We also conducted in vitro functional assays to assess TUBA1B's functional role in tumor cells, allowing for a detailed examination of its relationship with cancer prognosis and immune modulation. Results: Our findings indicate that TUBA1B expression is dysregulated across multiple cancers, correlating strongly with poor survival outcomes and advanced pathological stages. Functional enrichment analyses further revealed that TUBA1B regulates key cell cycle processes, driving tumor proliferation, migration, and invasion. It also influences immune functions within both the innate and adaptive immune systems, affecting immune-related signaling pathways. These insights underscore TUBA1B's multifaceted role in cancer progression and immune response. Conclusion: This study highlights TUBA1B's potential as a human oncogene with substantial roles in tumorigenesis and immune regulation. Elevated TUBA1B levels are associated with an immunosuppressive tumor microenvironment, impacting cancer progression and treatment outcomes. Targeting TUBA1B may offer promising therapeutic avenues for enhancing cancer treatment, offering new perspectives for innovative anti-tumor strategies with high clinical impact.

Lung adenocarcinoma, the most common subtype of lung cancer, is genomically complex, with tumors containing tens to hundreds of non-synonymous mutations. However, little is understood about how genes interact with each other to enable the evolution of cancer in vivo, largely due to a lack of methods for investigating genetic interactions in a high-throughput and quantitative manner. Here, we employed a novel platform to generate tumors with inactivation of pairs of ten diverse tumor suppressor genes within an autochthonous mouse model of oncogenic KRAS-driven lung cancer. By quantifying the fitness of tumors with every single and double mutant genotype, we show that most tumor suppressor genetic interactions exhibited negative epistasis, with diminishing returns on tumor fitness. In contrast, Apc inactivation showed positive epistasis with the inactivation of several other genes, including synergistic effects on tumor fitness in combination with Lkb1 or Nf1 inactivation. Sign epistasis was extremely rare, suggesting a surprisingly accessible fitness landscape during lung tumorigenesis. These findings expand our understanding of the interactions that drive tumorigenesis in vivo.

We report a case of acute myeloid leukemia with megakaryoblastic differentiation (AMKL) that developed after an initial B-lymphoblastic leukemia (B-ALL) with low hypodiploidy. Although the AMKL was initially thought either to be a phenotypic change from the original B-ALL or to have arisen as a result of treatment (acute myeloid leukemia, post cytotoxic therapy, AML-pCT [WHO]; AML, therapy related [ICC]), genetic evaluation of both the AMKL and the B-ALL suggest that neither of these considerations was correct. Rather, the AMKL did not harbor the most common genetic hallmark of AML-pCT-rearrangement of KMT2- and was genetically distinct from the B-ALL. Both the B-ALL and the AMKL, however, showed an identical TP53 mutation by next generation sequencing (NGS), while germline testing was negative for this mutant allele. Hence, either the patient had a tissue restricted constitutional TP53 mutation or had a somatic mutation in a multipotent hematopoietic precursor. This case highlights the necessity for close monitoring of patients with TP53-mutant tumors, as they may develop multiple lesions despite negative germline testing.

The hyperactive Wnt/β-catenin signaling circuit has been proven to be closely related to the progression of various cancers, with β-catenin serving as a central regulator of pro-tumorigenic processes. Preclinical evidences strongly support β-catenin as a promising therapeutic target. However, it has long been considered "undruggable" due to challenges such as the lack of crystal structures for its N- and C-terminal domains, high mutation rates, and limited availability of inhibitors. Notably, the network of β-catenin-associated protein-protein interactions (PPIs) is vital in the progression of multiple diseases. These interactions form a cancer-specific network that participates in all phases of oncogenesis, from cell metastasis to immunosuppressive microenvironment formation. Thus, researches on these PPIs are essential for unraveling the molecular mechanisms behind tumors with aberrant β-catenin activation, as well as for developing new targeted therapies. In this review, we delve into how β-catenin's PPIs orchestrate cancer progression and highlight biological and clinical dilemmas, proposing frontier technologies and potential challenges in targeting β-catenin for cancer therapy.

Myeloid neoplasms originate from the clonal proliferation of hematopoietic stem cells, which is driven by the acquisition of somatic genetic mutations. Within these disorders, myelodysplastic syndromes (MDS) are specifically characterized by morphological abnormalities (dysplasia) and impaired maturation of myeloid precursors (ineffective hematopoiesis), resulting in peripheral blood cytopenia. Several studies have advanced the field of MDS, with a few landmark papers leading to a paradigm shift, opening new avenues of research and enabling a molecular revolution. These seminal papers include the first description of the 5q- syndrome, the identification of somatic mutations of TET2 in myeloid neoplasms, the detection of common pathway mutations in the splicing machinery, and the discovery of clonal hematopoiesis. The somatic genomic landscape of MDS is now well defined. Genes that are recurrently mutated include epigenetic regulators, as well as genes of RNA splicing machinery, transcription regulation, DNA repair control, cohesin complex, and signal transduction. Furthermore, several disorders with a germline genetic predisposition to MDS have been identified, collectively accounting for up to 15% of all MDS cases. Genomic profiling can significantly improve the diagnostic approach to MDS, allowing the identification of distinct nosological entities such as SF3B1-mutant or TP53-mutant MDS. The Molecular International Prognostic Scoring System for MDS has already proven to be a valuable tool for individualized risk assessment and treatment decisions. In addition, the recently developed molecular taxonomy of MDS will likely facilitate the implementation of precision medicine approaches for these disorders. This will necessitate the establishment of specialized infrastructures within public health systems, involving close collaboration between healthcare institutions, academia, and the life-sciences industry.

Detection of molecular residual disease (MRD) allows for the identification of breast cancer patients at high-risk of recurrence, with the potential that early initiation of treatment at early stages of relapse could improve patient outcomes. The Invitae Personalized Cancer Monitoring™ assay (PCM) is a newly developed next-generation sequencing approach that utilizes up to 50 patient-specific, tumor-informed DNA variants, to detect circulating tumor DNA (ctDNA). The ability of the PCM assay to detect MRD before clinical relapse was evaluated.

The cohort included 61 female patients with high-risk breast cancer who underwent neoadjuvant chemotherapy. Plasma samples were collected before and during neoadjuvant therapy, after surgery and during monitoring. PCM was used to detect ctDNA at each time point.

The sensitivity to detect ctDNA in plasma from patients who relapsed during the monitoring phase was 76.9% (10/13). Specificity and positive predictive values were both 100% with all (10/61, 16%) of the patients who had ctDNA detected during the monitoring phase subsequently relapsing. Detection of ctDNA during monitoring was associated with a high-risk of future relapse (HR 37.2, 95% CI 10.5-131.9, p < 0.0001), with a median lead-time from ctDNA detection to clinical relapse of 11.7 months.

PCM detected ctDNA in patients who relapsed with a long lead-time over clinical relapse, shows strong association with relapse-free survival and may be used to identify patients at high-risk for relapse, allowing for earlier intervention.