Cancer research communications最新文献

Sarcomas in paediatric and adolescent-young adult populations represent rare and biologically heterogeneous tumours with complex genetic underpinnings.Genomic profiling reveals subtype-specific alterations and therapeutic targets.Such tumours still represent an unmet clinical need due to limited treatment options and poorer outcomes, especially in advanced stages.Here, we present the SAR-GEN2016 and SAR-GEN_ITA clinical trials, conducted across 12 Italian centres, which enrolled 201 patients including 158 bone and soft tissue sarcoma samples collected at diagnosis or relapse.Whole-exome sequencing was successfully performed on 120 tumour samples. The most representative histotypes were Osteosarcoma (OS, n=53),Ewing's sarcoma (EW, n=39),Rhabdomyosarcoma(n=13),and Synovial sarcoma (n=5),and the genomic analyses were mainly focused on these subtypes. Overall, our cohort showed genomic differences between subtypes, highlighting how genomic complex sarcomas and fusion-driven sarcomas are distinct entities. The genomic complex histotypes, such as OS, were characterised by a lower tumour mutational burden (TMB), and higher copy number variation burden with enrichment of the CN2 signature. Recurrent and metastatic EWs have a higher TMB compared to treatment-naïve primary tumours, along with increased intratumoural heterogeneity. Oncogenic pathway analyses revealed dysregulation of the RTK-RAS and NOTCH pathways across subtypes, particularly in metastatic and recurrent tumours. In 71 out of 120 analysed samples (59%), at least one potentially actionable genomic alteration was identified, and 16% of those patients with relapsed disease received a matched targeted therapy based on the molecular profiling results. All findings were classified as ESCAT Tier IIorIII. Our findings support the value of integrating genomic and clinical data to accelerate translational research in rare tumours.

Genome-wide coverage patterns of plasma cell-free DNA (cfDNA) fragments reflect nucleosome positioning in the cells of origin, enabling non-invasive inference of cell-type contributions and transcriptional activity. While the majority of cfDNA originates from hematopoietic cells, the diagnostic and biological relevance of this fraction remains underexplored. Here, we performed cfDNA-based deconvolution of blood cell types by integrating transcription start site (TSS) coverage profiles from plasma whole-genome sequencing with single-cell transcriptomic reference data. By correlating cfDNA TSS coverage with gene expression across 457 blood cell types, we ranked their relative contributions to the cfDNA pool. We analyzed 788 pre-treatment and longitudinal plasma samples from patients with localized colorectal cancer (CRC), muscle-invasive bladder cancer (MIBC), as well as 30 samples from healthy controls. In healthy individuals, cfDNA TSS coverage profiles reflected blood gene expression, and the inferred cell type contributions recapitulated the known hematopoietic composition. In cancer patients, we observed a significant increase in cfDNA contributions from lymphocytes, including T cells and plasma cells, and decreased contributions from monocytes and granulocytes. These immune-derived signatures distinguished CRC (AUC=0.793) and MIBC (AUC=0.745) patients from healthy controls. Longitudinal analysis of immune cell-type contributions revealed treatment-associated changes in the relative abundance of classical monocytes and plasma cells, although these temporal dynamics were not predictive of relapse or outcome. Together, these findings suggest that cfDNA-derived immune signatures may capture aspects of systemic immune remodeling in cancer, potentially providing a complementary non-invasive biomarker in liquid biopsies beyond tumor-derived signals.

Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase that targets p27 for proteasomal degradation, driving cellular proliferation. Knockout of Skp2 in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced anti-tumor immunity. Here, we applied single-cell RNA-sequencing (scRNA-seq) to primary OS tumors from Osx-Cre conditional Rb1/Trp53 knockout mice. We further compared with models of Skp2 disruption: Skp2 knockout or disruption of the Skp2-p27 interaction (resulting in p27 overexpression). We report that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. Skp2 disruption led to reduction of T cell exhaustion and upregulation of interferon signaling, as well as induction of cell-type specific replicative and endoplasmic reticulum stress, which we validated with proteomics analysis. Further, we showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased expression of metastasis-related gene signatures in Skp2-disrupted OS, which we validated by a strong reduction in lung metastasis in the Skp2 knockout mice. Finally, we report several mechanisms potentially used by OS to escape from Skp2 targeting, including upregulation of Myc targets, induction of genomic instability, overexpression of alternative E3 ligases, and lineage plasticity. These mechanistic insights into OS tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.

Real-world studies on desmoid tumors (DTs) are limited due to its low incidence. Therefore, we aimed to characterize the patient journey in DTs from diagnosis to treatment at an academic center in the United States. A retrospective cohort study was conducted at the University of Utah Health network. Eligible patients were diagnosed with DTs between 2011-01-01 and 2023-07-31, were ≥18 years old at diagnosis and had ≥2 DT-related encounters. Patient and tumor characteristics, reports of symptoms, and treatment patterns were abstracted from electronic health records. Healthcare resource utilization was quantified using administrative claims. Patients who potentially had a misdiagnosis ≤2 years before DT diagnosis were identified based on billing codes of conditions commonly diagnosed instead of DTs. Among 148 eligible patients, 59.5% had documentation of ≥1 DT-related symptom during the follow-up period. Pain was the most common reported symptom (57.4%). 79.7% of patients received ≥1 line of active treatment; some received up to 10 lines of therapy. Healthcare resource utilization was higher during periods of symptomatic disease and among patients with potential misdiagnosis (29.1%) in the year before DT diagnosis. Although surgery was the most common treatment, its use decreased across the study period with a corresponding expansion of systemic treatment modalities used as first line. In conclusion, increased healthcare resource utilization associated with misdiagnosis highlights the need for timely and accurate DT diagnosis. The varied treatment approaches and multiple lines of therapy suggest the need for optimal therapeutic agents. Surgery rates have decreased, aligning with evolving treatment guidelines.

Mitochondrial double-stranded RNA (mtdsRNA) is exported to the cytoplasm when mitochondrial RNA degradation is impaired, serving as a novel damage-associated molecular pattern (DAMP) for mitochondrial stress. Whereas mtdsRNA has been detected in certain cancers, its prevalence and functional role remain largely underexplored. Moreover, mtdsRNA is not readily detectable in large-scale computational datasets, reflecting technical limitations in the detection of structured mitochondrial transcripts. Here, we used comprehensive computational characterization of non-small cell lung cancer (NSCLC) cell lines and identified elevated light-strand transcripts in a subset of cell lines, suggesting a potential for mtdsRNA formation. We stratify NSCLC lines into groups with high and low mtdsRNA abundance. Despite high cytoplasmic mtdsRNA levels in select NSCLC cell lines, we did not identify significant correlation with mtdsRNA abundance and Type-I interferon (IFN-l) response. RT-qPCR analysis revealed that only USP18 transcripts amongst the IFN-l transcripts probed were significantly regulated in select NSCLC lines, indicating a partial or suppressed IFN-I response. Strand-specific RT-qPCR also revealed no bias in mitochondrial gene expression. These findings indicate that basal mtdsRNA accumulation alone is insufficient to trigger IFN-I signaling and may be tolerated in NSCLC, indicating adaptive mechanisms. Our findings suggest that mtdsRNAs could serve alternative non-immunogenic roles in tumor biology. Importantly, our work reports that mtdsRNA is upregulated in a subset of NSCLC cell lines and in other cancer cell types, suggesting that mtdsRNA may serve as a new marker of mitochondrial dysfunction in cancer.

Acute thrombocythemic myeloproliferative disease in mice has been reported upon introduction of Middle T gene expression of mouse polyomavirus. Merkel cell polyomavirus (MCPyV) is an oncogenic human polyomavirus that accounts for approximately 80% of all Merkel cell carcinomas. In this study, we assessed the presence of MCPyV DNA in fresh bone marrow (BM) aspirates from patients with myeloproliferative neoplasms (MPNs) using MCPyV-specific DNA polymerase chain reaction (PCR). MCPyV DNA prevalence was significantly higher in 78 BM samples from MPN patients (17.9%, 14/78) than in 66 BM controls undergoing femoral head replacement surgery (3%, 2/66; Fisher's exact test, p = 0.0063; OR = 7.95% confidence interval (CI) = 1.53-32.06). Notably, positivity was predominant in essential thrombocythemia (ET; 11/14). MCPyV mRNA was detected in MCPyV-DNA-positive samples, indicating low-level viral transcription. Interestingly, MCPyV positivity was significantly correlated with female sex but not with age or specific MPN genetic mutations, except for myeloproliferative leukemia virus oncogene (MPL) mutations. These findings suggest a potential association between MCPyV and MPNs, particularly ET, and support further investigation into the role of human polyomavirus in megakaryocytic lineage biology.

When tumor cells colonize distant organs during metastasis, they interact extensively with surrounding cells. These interactions often change the behavior of surrounding cell populations which collectively induce a pro-tumor microenvironment that permits tumor cell outgrowth into overt, clinically detectable metastatic disease. The lung is one of the most common sites of breast cancer (BC) metastasis. A chronic wound repair-related phenotype developed within the lung microenvironment during metastatic outgrowth in immunocompetent preclinical mouse models of BC. This phenotype was characterized by an increased number and activation of lung type II alveolar epithelial (AT2) cells surrounding growing metastases. Metastatic outgrowth significantly changed AT2 gene expression, resulting in a modified secretome. AT2-derived secreted factors also promote triple-negative breast cancer (TNBC) growth. AT2 secreted factors are regulated by the cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). Targeting CREB signaling with the phosphodiesterase 4 (PDE4) inhibitor roflumilast reduced AT2-BC reciprocal interactions in vitro and metastatic outgrowth in vivo. Finally, AT2 cells adjacent to metastases in lungs from patients with metastatic BC express higher PDE4B compared to AT2 cells in normal lungs.

KRASG12C inhibitors, such as sotorasib, show clinical efficacy for non-small cell lung cancer (NSCLC) positive for the G12C mutations of KRAS, but primary and acquired resistance to these drugs remains a clinical problem. We here show that development of resistance to sotorasib in KRASG12C-positive NSCLC cells was mediated by constitutive activation of EGFR resulting from downregulation of the protein tyrosine phosphatase receptor type R (PTPRR). PTPRR has been identified as a physiological regulator of ERK signaling in several cancer types. In our study, PTPRR was demonstrated to bind directly to EGFR, facilitating its dephosphorylation on tyrosine residues. Resumption of PTPRR expression in the resistant cells attenuated EGFR phosphorylation and restored sotorasib sensitivity. PTPRR downregulation was associated with gene promoter hypermethylation in the sotorasib-resistant cells and NSCLC tissue samples. Furthermore, low PTPRR expression in tumor specimens was associated with shorter progression-free and overall survival for NSCLC patients treated with sotorasib. In contrast to sotorasib, high PTPRR expression was associated with the poor response to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC, suggesting that PTPRR may broadly regulate EGFR dependence in NSCLC. Finally, dual blockade of KRASG12C and EGFR showed a substantial antitumor effect in a xenograft model of sotorasib-resistant NSCLC. This approach is therefore a rational therapeutic strategy for KRASG12C-positive NSCLC, especially for tumors showing PTPRR downregulation.

Risk classification in B-cell acute lymphoblastic leukemia (B-ALL) remains challenging, even in the era of genomic precision medicine. Current molecular classifiers fail to fully explain the heterogeneity in patient outcomes, suggesting that key regulatory layers remain hidden. Here, we uncover a previously unexplored dimension of B-ALL biology by analyzing co-expression patterns between pseudogenes using single-sample co-expression networks (n = 1,416). Principal component analysis showed that these interactions explain a major component of variability among patients and contribute to patient stratification into clusters with distinct overall survival. After identifying interactions associated with these clusters, we used a LASSO-based feature selection pipeline to derive a three-interaction signature that predicted patient survival, with RPL7P10-RPS3AP36 emerging as the most robust biomarker. Our study shows that co-expression between pseudogenes represents a previously unrecognized layer of molecular heterogeneity in B-ALL, harboring promising molecular markers for future studies.

Purpose: Biochemical recurrence (BCR) of prostate cancer (PCa) presents a clinical challenge with limited systemic treatment options beyond androgen deprivation therapy (ADT), which carries significant morbidity. Preclinical data suggest lysosomal homeostasis, including cholesterol trafficking and pH regulation, is a therapeutic vulnerability in hormone-dependent cancers. We therefore conducted HITMAN-PC, a phase I trial evaluating Suba-Itraconazole (SI) and hydroxychloroquine (HCQ) in men with BCR Patients and Methods:The synergy of SI and HCQ was validated in hormone-sensitive and castration-resistant prostate cancer cell lines. The HITMAN-PC trial then used a rolling-six design to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of HCQ with a fixed SI dose (150 mg twice daily). Secondary endpoints included safety, PSA kinetics (PSA-PFS, time to ADT), and exploratory pharmacokinetic and lipidomic profiling.

Results: Itraconazole showed dose-dependent cytotoxicity, with synergy in LNCaP-derived hormone-sensitive and resistant lines. Eleven patients were enrolled. Two dose-limiting toxicities at HCQ 600 mg twice daily (grade 3 diarrhea and ALT elevation) defined this level as the MTD with SI 150 mg twice daily. Common adverse events were hypertension, QTc prolongation, diarrhea, and nausea; no grade 4 events occurred. No PSA declines ≥50% were observed, though most patients achieved PSA stabilization. Median PSA-PFS, time to ADT, and metastasis-free survival were 5.5, 14.3, and 15.9 months, respectively. Lipidomic profiling revealed 240 treatment-associated lipid changes, with sphingomyelin and triacylglycerol species correlating with PSA-PFS.

Conclusions: Despite limited clinical activity overall, the identified lipidomic signatures provide proof-of-concept for using plasma lipidomics to monitor pharmacodynamic activity in future metabolism-targeted trials.