Tumor deposits are irregular clusters of tumor cells in adipose tissue, discontinuous from the primary tumor. While their prognostic relevance has been well established in colorectal and gastric cancers, their significance in breast cancer remains poorly understood. This case highlights the presence of tumor deposits in breast cancer, with focus on their potential prognostic implications as well as the need for clearer diagnostic criteria.

We report the case of a 58-year-old Tunisian woman who presented with a 2-cm breast nodule. Clinically, the lesion was staged as T4bN0Mx, and imaging classified it as American College of Radiology category 5. Fine needle biopsy revealed an invasive grade III breast carcinoma according to the Scarff-Bloom-Richardson grading scale. The patient received hormone therapy, radiotherapy, and neoadjuvant chemotherapy followed by mastectomy with axillary dissection. Histopathological examination of axillary adipose revealed 14 tumor deposits and five metastatic lymph nodes with extracapsular extension. The pathological response to chemotherapy was poor, with more than 50% residual tumor. The patient is currently in good condition and is receiving hormone therapy.

Although tumor deposits are correlated with poor prognosis in other cancers, particularly in colorectal and gastric cancer, limited data are available for breast cancer. Owing to the unclear diagnostic criteria, they are often considered as lymph node metastases. To address this issue, we recommend reporting tumor deposits, and we encourage further studies on larger cohorts to better define their prognostic value and eventually, discuss their inclusion in the tumor, node, metastasis staging system.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized oncology by achieving durable remissions in refractory hematologic malignancies. However, emerging reports link this therapy to second primary malignancies, including CAR+ lymphomas and leukemias, driven by insertional mutagenesis from semi-random viral vector integration near oncogenes or tumor suppressor loci. These rare but serious complications underscore the dual challenge of eradicating primary tumors while mitigating delayed genotoxic risks. Conventional CAR-T cell manufacturing, reliant on gamma-retroviral or lentiviral vectors, introduces genomic instability through integration into fragile sites or transcriptionally active regions. CRISPR/Cas9-mediated genome editing further amplifies risks via off-target double-strand breaks and chromosomal rearrangements. This review evaluates genomic safe harbors (GSHs)-such as AAVS1, TRAC, CCR5, ROSA26 and CLYBL-as loci validated for stable, high-level CAR transgene expression without oncogenic disruption. GSHs meet stringent criteria: distal from cancer-related genes, resistant to epigenetic silencing, and transcriptionally permissive. Preclinical studies demonstrate that site-directed CAR integration into GSHs preserves antitumor efficacy while eliminating malignant transformation risks. Challenges persist in optimizing homology-directed repair efficiency, mitigating residual dsDNA toxicity, and standardizing regulatory frameworks for long-term genomic surveillance. Emerging technologies-base/prime editing, hybrid nucleases, and rigorous monitoring-promise enhanced precision and safety. By reconciling therapeutic innovation with genomic integrity, GSH-engineered CAR-T cells herald a paradigm shift toward precision immunotherapies, offering curative potential while preempting secondary oncogenesis. Collaborative efforts to refine manufacturing, harmonize global standards, and prioritize patient-specific risk stratification will be critical to advancing this transformative approach.

Epidemiological studies have shown a small but significantly increased risk of leukemia in children conceived by in vitro fertilization. Atypical DNA methylation patterns observed in pediatric cancers are suspected to occur in utero, and it is known that periconceptional conditions linked to assisted reproductive technologies (ART) are responsible for DNA methylation modifications.

Using databases and systematic literature screens, we derived a list of cancer/leukemia genes (n = 1246 and n = 532 genes, respectively, corresponding to 1466 individual genes) and of differentially methylated genes (DMG) in leukemia (n = 2642) and pre-leukemia (n = 381). These lists were cross-referenced with DMG (n = 93) curated from 18 ART Epigenome-Wide Association Studies (EWAS) (2369 samples). Among the ART DMG, more than one-third (n = 33) were leukemia, and six were pre-leukemia DMG, all representing a significant enrichment. Seven of the enriched genes (NTM, PRSS16, SCAND3, SYCP1, TP73, ZNF184, and ISL1-DT) showed concordant methylation between ART and leukemia/pre-leukemia. Moreover, five of the ART DMG are known targets for somatic/germline alterations in leukemia: ATP10A, CHD2, FBRSL1, FGFR2, and SORCS1. The ART DMG were not significantly enriched in cancer genes, supporting the hypothesis that ART may not link broadly to any cancer type but rather to leukemia.

This study indicates that relatively few genes that are known targets for somatic/germline mutation in cancer experience DNA methylation changes in individuals conceived through ART. By contrast, DNA methylation disturbances reported in leukemia represent more than one-third of those associated with ART conception, thus raising the question of their role in leukemia risk in ART-conceived individuals. Among them, a few critical genes such as TP73, a tumor suppressor, were shown to be targeted for hypermethylation, both in ART and leukemia, warranting further investigation.

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, remains uniformly fatal due to the lack of effective targeted therapies. The epidermal growth factor receptor (EGFR) is the most frequently altered receptor tyrosine kinase oncogene in GBM with most alterations impacting the receptor ectodomain function, including gene amplification, mutation, rearrangement, and splicing site changes, which occur in approximately 50% of GBM tumors. Depatuxizumab mafodotin (Depatux-M; ABT-414), an antibody-drug conjugate composed of an EGFR-specific antibody (ABT-806) that recognizes the EGFR ectodomain linked to the cytotoxic agent monomethyl auristatin F, initially showed clinical promise. However, it failed to improve survival in phase III trials, highlighting an urgent need to understand mechanisms of resistance.

We generated in vivo ABT-414 resistant GBM models using patient-derived xenografts (PDXs) and performed genomics and transcriptomic profiling, including whole exome sequencing, bulk RNA sequencing, and single-cell RNA sequencing.

ABT-414-resistant tumors exhibited transcriptional reprogramming characterized by upregulation of synaptic and developmental gene networks and downregulation of biosynthetic processes, indicative of a plastic, therapy-adaptive state. Whole-exome sequencing revealed novel mutations exclusive to resistant tumors, including a recurrent TEK (TIE2) S466I point mutation present in all ABT-414 resistant GBM12 PDX tumors. Functional validation demonstrated that ectopic expression of TEK S466I and TEK WT in PDX models reduced EGFR levels, suggesting a novel feedback mechanism linking TEK signaling to EGFR downregulation and contributes to resistance.

Our findings demonstrate that resistance to ABT-414 arises through both adaptive transcriptional remodeling and newly acquired genetic alterations. TEK-mediated suppression of EGFR represents a previously unrecognized mechanism of resistance, with potential implications for overcoming antibody-drug conjugate failure in GBM.

Colorectal cancer liver metastasis (CRLM) is associated with poor survival, primarily due to acquired therapy resistance. While novel therapies arise, translation is limited by the lack of tumor models accurately representing dynamic microenvironmental interplay. Here, we show that ex vivo normothermic machine perfusion (NMP) offers a novel preclinical framework to study the intratumoral dynamics of CRLM biology.

Six resected metastatic human livers were preserved for two days and subjected to multi-omic profiling of serially sampled adjacent liver and metastatic tissue using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST). Tissue integrity was assessed and cross-validated by immunofluorescence (IF), high-resolution respirometry (HRR) and flow-cytometry.

NMP was successfuly applied to metastatic livers with minimal surgical adaptations, preserving both intrinsic hepatic properties and tissue viability over an extended duration. Single-cell and spatial mapping confirmed preservation of CRLM phenotypic properties and demonstrated high clinical translatability by applicability of the intrinsic epithelial consensus molecular subtypes to metastasis. Spatially deconvoluted pathway activities reflected functional tissue-microenvironments. Transcriptomic profiles - including those of tumor-associated myeloid cells - were preserved during NMP. Finally, we demonstrate tumor-associated myeloid cell persistence as a driver of disease progression and poor survival in colorectal cancer.

Our findings represent the basis for future innovative applications adopting NMP in the context of CRLM, providing a new preclinical tumor model avenue.

Resistant mutations and amplification of the epidermal growth factor receptor (EGFR), followed by the upregulation of its translated protein undermines the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma (LUAD). This underscores that promoting EGFR protein degradation may be a promising strategy for treatment.

Ubiquitin ligases database analysis identified NEDD4L as a mediator of EGFR proteasomal degradation, which was further confirmed by qPCR, western blot, immunofluorescence staining and CO-IP. The upstream regulatory role of FOXM1 on NEDD4L was elucidated through bioinformatics analyses and validated using dual luciferase reporter assay, ChIP, qPCR, western blot and immunohistochemistry. Virtual screening and molecular docking were used to identify inhibitors of FOXM1. Functional studies and therapeutic strategies were conducted using gain- and loss-of-function assays, and evaluated through in vitro and in vivo experiments.

We identified the E3 ubiquitin ligase NEDD4L that targets both wild-type EGFR and osimertinib-sensitive/resistant EGFR mutants for proteasomal degradation, thereby effectively inhibiting EGFR-driven LUAD growth. We found FOXM1 as a critical upstream transcription factor that binds to the promoter of NEDD4L and represses its expression, further promoting tumor growth and osimertinib resistance in LUAD by increasing EGFR protein level. High FOXM1 expression correlates with low NEDD4L expression in LUAD patients, which is associated with poor clinical outcomes. Notably, we further identified that verteporfin, an FDA-approved small molecule drug, as a FOXM1 inhibitor. Verteporfin suppresses FOXM1 to upregulate NEDD4L expression and facilitate EGFR proteasomal degradation, thereby inhibiting EGFR-driven LUAD growth and overcoming osimertinib resistance. Remarkably, the combination of verteporfin and osimertinib shows an additively inhibitory effect on EGFR-mutated LUAD growth compared to monotherapy, both in post-TKI resistance and upfront treatment settings.

This study demonstrates that FOXM1/NEDD4L axis impairs EGFR proteasomal degradation, thus contributing to EGFR-driven LUAD growth and osimertinib resistance. Combination therapy incorporating NEDD4L activation may represent a new valued therapeutic strategy for EGFR-driven LUAD and osimertinib resistance.

Renal cell carcinoma (RCC) poses significant challenges to precision oncology due to its pronounced molecular heterogeneity and complex tumor microenvironment (TME). Traditional two-dimensional (2D) cultures and animal models fall short in capturing patient-specific tumor biology, limiting their translational relevance. In contrast, three-dimensional (3D) organoid platforms offer structurally and functionally representative models that retain key pathological and pharmacological features of RCC. Notably, RCC organoids enable pharmacokinetic assessment, including drug penetration, metabolic activation, and off-target toxicity in a spatially organized context. This review outlines current strategies for RCC organoid construction-including patient-derived organoids (PDOs), air-liquid interface (ALI) cultures, scaffold-based matrices, and microfluidic systems-and evaluates their applications in drug screening, resistance modeling, and immunotherapy prediction. We further discuss technical and biological limitations such as phenotypic drift, inter-sample variability, and TME reconstruction, alongside emerging solutions in synthetic scaffolds, immune co-cultures, and multi-omics integration. In conclusion, RCC organoids are rapidly evolving into clinically actionable platforms, offering a scalable and predictive approach to personalized therapy in renal oncology.

Ameloblastic fibroma (AF) is a rare benign odontogenic tumor characterized by the coexistence of epithelial and mesenchymal components, typically arising intraosseously in the posterior mandible during the first two decades of life. Its peripheral variant, occurring extraosseously in gingival soft tissue without bone involvement, is exceedingly rare. Owing to its clinical resemblance to reactive gingival lesions, peripheral AF poses diagnostic challenges and is frequently misdiagnosed without histopathological confirmation.

We report a case of peripheral AF in a 34-year-old Chinese woman who presented with a slow-growing, asymptomatic soft tissue mass on the palatal gingiva between teeth 23 and 24. Clinical examination revealed a well-defined, sessile lesion measuring 6 mm × 6 mm, with no signs of pain, bleeding, or tooth mobility. Radiographic evaluation, including panoramic imaging and cone beam computed tomography, confirmed the absence of bone involvement. The lesion was excised under local anesthesia, followed by root planing and soft tissue reconstruction using a laterally positioned flap to preserve esthetics. Histopathological examination demonstrated classic features of AF, including epithelial strands and cords within a cell-rich ectomesenchymal stroma, with peripheral palisading and central stellate reticulum-like cells. Immunohistochemistry revealed low Ki-67 proliferation index and negative BRAF expression, supporting the benign nature of the lesion. The final diagnosis was peripheral ameloblastic fibroma. Follow-up over 20 months showed no recurrence and excellent gingival healing with preserved architecture.

This case underscores the importance of considering peripheral AF in the differential diagnosis of gingival masses, particularly those mimicking reactive lesions. Histopathological and immunohistochemical analyses are essential for accurate diagnosis and appropriate management. Conservative surgical excision with careful flap design can achieve excellent functional and esthetic outcomes. Given its rarity, every well-documented case of peripheral AF contributes meaningfully to the understanding of its clinical behavior and optimal treatment strategies.

Cancer development is a complex process, initiated by the combination of epigenetic and genetic changes in normal cells. Selective microenvironmental pressure within the primary tumors prompts the microevolution of invasive cell lineages that efficiently penetrate circulation and lymphatic systems and extravasate in distant organs, initiating the formation of metastases. Extravasation (diapedesis), i.e., the multistep penetration of the endothelial layer by circulating cancer cells, is regarded as the decisive step and one of the bottlenecks of the metastatic cascade. It limits malignant cancer dissemination, while initiating the formation of metastases. The efficiency of extravasation depends equally on the properties of circulating cancer cells and the local functional status of the endothelium, which remains sensitive to paracrine, adhesive, and juxtacrine stimuli generated by cancer and immune cells. Here, we review the current state of knowledge on the significance of endothelial activation for the diapedesis of circulating cancer cells, with the emphasis on the intercellular communication pathways that mediate this process. We also address the potential and limitations of endothelial activation as the target for novel strategies of cancer treatment.

The WNT signaling pathway, a fundamental molecular network regulating cell proliferation, differentiation, and stemness, plays a critical role in tumorigenesis, cancer progression, and therapeutic resistance. Given its crucial regulatory roles in tumors, WNT signaling pathway has been identified as effective targets for cancer treatment. However, the current clinical efficacy of WNT signaling pathway-targeted anti-tumor therapies remains suboptimal. Based on research investigating the role of WNT signaling pathway in cancer, we systematically discuss the molecular mechanisms of WNT signaling in cancer (including both canonical and non-canonical signaling pathways), the role of WNT signaling in different cancer types, highlighting distinct potential therapeutic approaches targeting WNT signaling. We also comprehensively review innovative strategies targeting WNT signaling, including Porcupine (PORCN) inhibitors, Tankyrase (TNKS) inhibitor, Frizzled (FZD)-targeted monoclonal antibodies, β-catenin/TCF transcriptional complex inhibitors, and natural bioactive compounds and drug repositioning etc., critically evaluating their preclinical efficacy and limitations. We emphasize the need for and challenges in developing WNT-targeted therapies including refining the specificity of WNT signaling pathway-targeted therapies, developing biomarkers for patient selection, and exploring synergies between WNT inhibitors and other therapeutic modalities such as immune checkpoint blockers. These advances aim to enable personalized precision therapy and revolutionize cancer treatment paradigms in the future.