Cancer research communications最新文献

Low-pass whole-genome sequencing (LP-WGS) of circulating tumor DNA (ctDNA) is increasingly recognized for its utility in identifying somatic copy-number aberration (CNA). In this study, we analyzed LP-WGS ctDNA data from 73 pediatric patients with neuroblastic tumor and 11 healthy controls to explore diagnostic value of ctDNA CNA burden (including the genotypings) with a customized bioinformatics workflow. We found that a high baseline ctDNA CNA burden [tumor DNA fraction (TFx) ≥0.2%] was present in 36 of 41 patients (87.80%) with neuroblastoma, six of 22 patients (27.27%) with ganglioneuroblastoma, and three of 10 patients (30%) with ganglioneuroma. High baseline ctDNA CNA burden could predict high-risk neuroblastic tumors with an area under curve (AUC) of 0.95, sensitivity of 94.12%, and specificity of 100%. Frequent chromosomal copy-number changes, including chr17q gain, chr7 gain, chr3p loss, and chr11q loss, were found in ctDNA. Gain of chr17q demonstrated the highest diagnostic value with an AUC of 0.92, indicating strong sensitivity and specificity for detecting high-risk neuroblastic tumors. The homologous recombination deficiency score in the high- and intermediate-risk groups was significantly elevated compared with those in the low-/very low-risk group. The TFx levels and segmental alterations significantly decreased in patients with neuroblastic tumor who underwent chemotherapy, from median TFx = 13.82% before treatment to 0.24% after treatment (P < 0.0001). Our findings highlight the effectiveness of LP-WGS ctDNA CNA analysis as a promising approach for diagnosis and risk stratification of pediatric neuroblastic tumors and for monitoring chemotherapy response. Particularly, ctDNA analysis is minimally invasive, rapid, and cost-effective, which could bring additional benefits in pediatric practices.

Significance: Our results support the development of ctDNA CNA analysis as a robust and minimally invasive approach for early detection, molecular diagnosis, and risk stratification of peripheral neuroblastic tumors.

The aim of this study was to test whether intratumoral heterogeneity explains inconsistent reports on VEGF-A as a prognostic marker in laryngeal squamous cell carcinoma (LSCC) and to identify expression phenotypes (mRNA/miRNA) associated with recurrence. In a prospective cohort of 60 patients with T3/T4 LSCC undergoing primary laryngectomy, we sampled four regions per case (tumor surface, tumor depth, peritumoral mucosa ≤1 cm, and paired distant normal mucosa). mRNA levels of hypoxia-inducible factor (HIF) 1α/2α/3α, VEGF-A, VEGFR1/2, and ETS-1 were quantified by qRT-PCR; cohort-matched miRNA profiling (microarray with qRT-PCR validation) was integrated. Elevated VEGF-A at tumor depth predicted recurrence (log-rank P = 0.0001), whereas surface VEGF-A had no prognostic value (P = 0.170). Pairwise testing confirmed higher VEGF-A at depth versus surface (Wilcoxon P = 0.026). A subgroup with depth VEGF-A relative quantification (RQ) > 2 and HIF1α RQ < 2 showed a 64% recurrence rate. An independent subgroup defined by high miR-93-5p/miR-144-3p/miR-210-3p expression also had significantly worse outcomes. The two subgroups were non-overlapping in most patients and accounted for 76% of recurrences. The prognostic relevance of VEGF-A in LSCC is region dependent, with clinically meaningful value confined to tumor depth. Together with a high-risk three-miRNA signature, these findings delineate two molecular subgroups capturing most recurrences and may inform sampling strategies and risk stratification.

Significance: We demonstrate that VEGF-A has prognostic value in laryngeal carcinoma only when assessed at tumor depth. Alongside a distinct high-risk miRNA signature, we define two molecular subgroups accounting for most recurrences, highlighting the clinical importance of spatial heterogeneity in biomarker evaluation.

Urokinase plasminogen activator receptor-associated protein (uPARAP) is a collagen-internalizing receptor with emerging relevance as a therapeutic target. The involvement of uPARAP in extracellular matrix turnover and stromal remodeling within the tumor microenvironment (TME) makes it an especially promising target in tumors with a high stromal component. Mesothelioma, characterized by its unique complex TME, is a highly refractory cancer type for which no effective targeted therapy exists. uPARAP has been shown to be expressed across all subtypes of mesothelioma, especially in the sarcomatoid and biphasic subtypes, suggesting that a uPARAP-targeted therapy may benefit a specific patient population. In this study, we utilized an antibody-drug conjugate (ADC) comprising an anti-uPARAP mAb conjugated to monomethyl auristatin E via a protease-sensitive linker for preclinical studies on mesothelioma treatment. Using mouse xenograft models with a human mesothelioma cell line or a patient-derived mesothelioma cell isolate, we demonstrated a strong anticancer effect following treatment with the uPARAP-targeting ADC. IHC studies revealed this to be the case, even in tumors exhibiting a heterogeneous expression of uPARAP, suggesting that uPARAP-expressing cancer-associated fibroblasts also play a role in the anticancer effect through a bystander mechanism. Furthermore, we show that combination treatment with cisplatin, commonly used in first-line mesothelioma therapy, leads to a strongly enhanced anticancer effect relative to treatment with either drug alone. Our study demonstrates the potential utility of a uPARAP-targeted ADC as a therapeutic option for mesothelioma, alone or in combination with chemotherapeutics. This perspective is particularly emphasized by a recently initiated clinical trial with a humanized anti-uPARAP ADC for the treatment of other malignancies.

Significance: This study highlights the translational promise of a uPARAP-targeted ADC for the treatment of mesothelioma, a cancer lacking effective therapies. Demonstrating potent preclinical efficacy and synergy with cisplatin, our findings support the clinical advancement of a uPARAP-directed ADC strategy, particularly considering an ongoing clinical trial evaluating this approach in other malignancies.

Bone metastases represent a common and devastating complication of breast cancer; however, the immune determinants of skeletal colonization, particularly the role of adaptive lymphocyte subsets, have only recently been elucidated. In this study, we identified a nonclassical regulatory role of CD19+ B cells in the modulation of bone remodeling and breast cancer metastatic progression. Using murine models of metastatic 4T1 and nonmetastatic 67NR mammary tumors, we show that 67NR-bearing mice exhibit increased trabecular bone mass, associated with osteoprotegerin (OPG) secretion by CD19+IgD+IgM+CD138- B cells. Functional assays demonstrated that 67NR-primed B cells suppressed bone resorption in vitro and counteracted 4T1-specific T cell-mediated osteolytic activity in vivo. Adoptive transfer of 67NR-primed CD19+ B cells into 4T1-bearing immunocompetent or immunodeficient hosts preserved bone architecture, reduced RANKL production, inhibited metastases, and limited tumor growth. These effects are T cell-independent at the effector phase but require T cell-licensing for the acquisition of the OPG-producing phenotype. Silencing OPG abrogated this protective function. Mechanistically, B cells must be transferred during the early stages of tumor progression to retain their therapeutic potential. Molecular analyses supported the enrichment of RANKL+CD4+ T cells in tumors and lymph nodes, whereas OPG+ B cells were restricted to tumors. Transcriptomic data from The Cancer Genome Atlas further support the prognostic relevance of these immune phenotypes. In a retrospective human cohort, high RANKL+ lymphocyte infiltration in primary tumors correlated with bone metastases, whereas OPG+ infiltration predominated in bone metastasis-free cases. These findings uncover a B cell-driven axis that restrains osteolysis and tumor progression.

Significance: This study identifies opposing RANKL+ T cell and OPG-producing B cell immune phenotypes that shape bone metastasis risk in breast cancer. By revealing how these adaptive lymphocyte subsets influence osteolysis and skeletal colonization, our findings define prognostic immune signatures with potential utility for early risk stratification and clinical decision-making.

Cancer stem cells (CSC) are hypothesized to promote tumor progression through innate chemoresistance and self-renewal. CSCs reside in the CD34+/CD38- immunophenotypic subpopulation of acute myeloid leukemia (AML). Isolation of CSCs from B-lymphoblastic leukemia (B-ALL) has proven difficult, and the cells of interest apparently are not isolated to the CD34+/CD38- compartment. This may be explained, in part, by temporal variations of CD34 and CD38 expression which result in stochastic cell state transitions (e.g., from CD34+/CD38+ to CD34+/CD38-). We present a mathematical model of these transitions and correlate salient findings with BCR::ABL1 status, minimal residual disease (MRD), and relapse in adult B-ALL. As the CSC hypothesis is well supported in AML, we focus on transitions to and from the hematopoietic stem cell compartment (CD34+/CD38-). Our analysis suggests the presence of dedifferentiating transitions to a CD34+/CD38- stem cell-like immunophenotype, especially in B-ALL with BCR::ABL1. In contrast, BCR::ABL1-negative patient samples have low CD34+/CD38- self-renewal rates and either high CD34+/CD38+ or CD34-/CD38+ incoming rates. High CD34+/CD38- self-renewal is also associated with positive MRD following induction chemotherapy. We find a lack of observable changes in cell state transitions between diagnosis and relapse specimens. Furthermore, simulated therapies targeting the stem cell-like compartment indicate that blocking transitions to the CD34+/CD38- state (i.e., blocking dedifferentiation) is more effective than promoting transitions from the CD34+/CD38- state toward other states (i.e., promoting differentiation) to reduce the proportion of CD34+/CD38- cells. The modeling framework used here is a novel, useful tool to infer prognosis and genotype from routine flow cytometry.

Significance: Flow cytometry characterization of B-ALL samples (diagnosis, remission, and relapse) is used to parameterize a mathematical model of cell state transition rates and stratify patients for post-induction chemotherapy MRD.

We previously generated an orthotopic, NF2-deficient meningioma model using the luciferase-expressing Ben-Men-1 cell line established from a sporadic tumor and identified the multikinase inhibitor brigatinib and the mTOR kinase inhibitor INK128 to potently impede tumor growth. In this study, we describe generation of the telomerase-immortalized AG-NF2-Men cell line from a grade-1 meningioma of a patient with NF2-related schwannomatosis (NF2-SWN). We showed that like Ben-Men-1 cells, AG-NF2-Men cells were NF2-null, expressed several NF2-regulated receptor tyrosine kinases, and responded to their cognate ligands. We also found that brigatinib and INK128 alone inhibited AG-NF2-Men cell proliferation at IC50 values similar to those in Ben-Men-1 cells. Combining brigatinib with INK128 exhibited growth-inhibitory synergy. Mechanistically, the combination not only completely abrogated p-AKT(S473) and its downstream signaling compared with either drug alone but also prevented INK128-mediated rephosphorylation of AKT on T308. Also, the combination more effectively blocked ligand-mediated phosphorylation of EGFR, ErbB3, and IGF-1R and elicited major changes in the expression of genes, including the upstream regulators of several signaling networks important for meningioma growth. Furthermore, we generated luciferase-expressing AG-NF2-Men cells that readily grew as intracranial xenografts. Importantly, combining brigatinib with INK128 enhanced tumor regression in both the orthotopic AG-NF2-Men and Ben-Men-1 xenograft models. As the first NF2-SWN-related meningioma cell line, AG-NF2-Men is a unique reagent for investigating meningioma biology and therapeutics. A clinical trial to evaluate the combination of brigatinib with an mTOR inhibitor in NF2-deficient meningiomas is warranted.

Significance: AG-NF2-Men represents the first NF2-SWN-related meningioma model. The brigatinib + INK128 combination exhibits antitumor synergy in both the AG-NF2-Men and Ben-Men-1 meningioma models, suggesting combining brigatinib with mTOR inhibition to more effectively treat NF2-SWN and sporadic NF2-deficient meningiomas.

Molecular signatures predict prognosis in hepatocellular carcinoma, but their relevance to transarterial radioembolization (TARE) with yttrium-90 (90Y) is unknown. We aimed to identify baseline and treatment-induced pathways associated with response and nominate biomarkers. Ten transcriptomically diverse human liver cancer cell lines were exposed to escalating activities of glass 90Y microspheres for 10 days. Normalized AUC values quantified sensitivity. Whole-transcriptome RNA sequencing at baseline and after treatment was analyzed with elastic net regression and gene set enrichment. Findings were corroborated by qRT-qPCR and exploratory analysis of pretreatment tumor samples from patients undergoing TARE. Liver cancer cell line responses to 90Y were heterogeneous, with resistance aligning to Hoshida S1 and cholangiocarcinoma-like subtypes. Epithelial-mesenchymal transition (EMT) and adhesion pathways were enriched in resistant lines, with CD44 and ITGA3/α3β1 emerging as candidate markers, corroborated by RNA and protein expression. After 90Y exposure, resistant lines upregulated IFNγ/α, TNFα/inflammatory, and antigen presentation-related pathways, whereas sensitive lines downregulated these pathways along with DNA repair and oxidative phosphorylation. In an exploratory patient cohort, higher tumor CD44 expression trended with early progression. In conclusion, liver cancer cell lines display marked biological heterogeneity in response to 90Y. Baseline EMT/adhesion signatures and stress response pathways nominate CD44 and ITGA3/α3β1 as candidate biomarkers of resistance. These findings delineate molecular programs of β-emitter radioresistance and identify candidate pathways for future targeting.

Significance: TARE with 90Y is widely used for liver cancer, yet its molecular determinants of response are poorly understood. Using a diverse panel of liver cancer cell lines, we identify EMT, adhesion, and stress response pathways associated with resistance. These findings highlight candidate biomarkers and molecular vulnerabilities that may guide future therapeutic strategies and patient selection.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite improved therapies, refractory and relapsed ALL remain the leading cause of cancer-related mortality in children. There is a need for accessible biomarkers for frequent, minimally invasive disease monitoring and prompt intervention. MicroDNA is a novel extrachromosomal DNA that preferentially originates from gene segments with high transcriptional activity and/or increased chromatin accessibility. We investigated whether microDNA-producing genes repertoire changes in a disease-dependent manner. We characterized microDNAs in 52 paired bone marrow (BM) and plasma samples from pediatric patients with ALL at diagnosis, relapse, and remission. No difference in the length or number of microDNA was noted across stages, but comparative analysis of microDNA profiles led to the identification of microDNA gene panels associated with active disease. The relative distribution of these genes was significantly different from that expected by chance (P < 0.0001). Analyses of BM samples identified a signature comprising 289 distinct microDNA-producing genes present in multiple patients at diagnosis and relapse but absent in remission. The best biomarker candidates were 11 microDNA-producing genes identified also in plasma samples at diagnosis and overrepresented in patients who relapsed (P = 0.006). MicroDNA from the same genes was confirmed in relapse plasma samples. All signature genes are known to be involved in cancer proliferation or drug response. MicroDNA seems to be a candidate for a novel class of biomarkers for ALL, with the potential to improve precision diagnostics, particularly through their identification in plasma samples. Further validation in an independent cohort of patients is warranted.

Significance: Despite high cure rates, 10% to 15% of pediatric patients with ALL experience relapse. We identified a plasma-detectable microDNA signature from 11 genes that persists from diagnosis through relapse but disappears in remission. These findings demonstrate the potential of microDNA profiles as prognostic biomarkers in pediatric ALL, enabling noninvasive monitoring of disease status and risk stratification.

Deregulation of proteins involved in chromatin regulation is common in pancreatic ductal adenocarcinoma (PDAC). Lysine demethylase 4C (KDM4C) is one of the chromatin-modifying proteins frequently overexpressed across multiple solid cancers and is linked to chromatin instability, increased cell proliferation, and enhanced stem cell-like behavior. We observed upregulation of KDM4C protein in a panel of human PDAC cell lines and patient samples compared with nonneoplastic controls. CRISPR/Cas9-mediated deletion of KDM4C in human and murine PDAC cells reduced proliferation, clonogenicity, and increased survival of orthotopically implanted murine PDAC allografts. Transcriptomic and proteomic analyses revealed that loss of KDM4C in both human and murine PDAC cell lines was associated with the reduction of activated phospho-ERK, a pivotal effector downstream of mutant RAS. Using proximity labeling, we identified the histone deacetylase SIRT1 as a novel interacting protein with KDM4C via the latter's Tudor reader domain. SIRT1-mediated deacetylation leads to repression of downstream targets, including the dual specificity phosphatase DUSP2, which is known to inactivate ERK via dephosphorylation. In vitro propagation of KDM4C-null PDAC lines eventually led to adaptation and restitution of ERK signaling, with rescue of the KDM4C loss induced growth suppression. To bypass this adaptive phenomenon, we tested a preclinical pan-KDM4 inhibitor TACH107 and confirmed its efficacy in in vitro and in vivo PDAC models. Our studies identify KDM4C as an oncogenic molecule that sustains ERK signaling in KRAS-mutant PDAC and can be broadly targeted via small-molecule inhibitors.

Significance: Our data suggests that KDM4C is a novel regulator of ERK signaling, the main effector pathway downstream of mutant RAS. This is the first demonstration linking the requirement of sustained KDM4 activity to ERK signaling in cancer and presents an opportunity to leverage this oncogenic pathway for therapeutic intervention.

The role of androgen receptor (AR) signaling in modulating antitumor immune responses has received increasing attention in recent years; however, its broader impact across diverse cancer types and between sexes remains largely unexplored. In this study, we investigated how AR activity correlates with tumor-infiltrating leukocytes, patient prognosis, and immunotherapy response across cancers and sexes. We inferred AR activity using a network-based approach across bulk RNA sequencing [RNA-seq; The Cancer Genome Atlas (TCGA)], single-cell RNA-seq (prostate cancer meta-atlas), and immunotherapy cohorts. Pathway analysis and Cox regression assessed mechanisms and survival. Immune infiltration and signatures were evaluated via TIMER and single-sample gene set enrichment analysis. Key findings were validated using digital spatial profiling and IHC. Our pan-cancer analysis of 33 TCGA cancer types revealed broad variability in AR activity, with highest observed in prostate adenocarcinoma. Genes significantly correlated with AR activity showed negative associations and were enriched in immune activation pathways. Notably, AR activity inversely correlated with leukocyte abundance and IFNγ pathway activity across tumors and sexes-unlike estrogen or progesterone receptors. Longitudinal biopsy analysis in metastatic prostate cancer showed that AR inhibition enhanced immune cell and IFNγ signatures. Single-cell analysis confirmed that tumor-intrinsic AR activity inversely correlates with immune infiltration in prostate cancer. Furthermore, low AR activity is significantly associated with favorable immunotherapy responses in hormone-independent cohorts. Spatial proteomics showed a negative correlation between AR and CD45 protein in sarcoma and ovarian cancers. These findings suggest AR activity as a pan-cancer predictive biomarker of immunotherapy response and support that AR blockade in immunotherapy-refractory tumors represents a promising treatment strategy, regardless of tumor type or patient sex.

Significance: Tumor-associated AR activity negatively correlates with immune infiltration and immunotherapy response across cancers, independent of sex, suggesting that combining AR inhibitors with checkpoint blockade may benefit patients with immunotherapy-refractory tumors.