Cancer research最新文献

Radiotherapy is an integral component in the treatment of many types of cancer, with approximately half of patients with cancer receiving radiotherapy. Systemic therapy applies pressure that can select for resistant tumor subpopulations, underscoring the importance of understanding how radiation impacts tumor evolution to improve treatment outcomes. We integrated temporal genomic profiling of 120 spatially distinct tumor regions from 20 patients with undifferentiated pleomorphic sarcomas (UPS), longitudinal circulating tumor DNA analysis, and evolutionary biology computational pipelines to study UPS evolution during tumorigenesis and in response to radiotherapy. Most unirradiated UPSs displayed initial linear evolution, followed by subsequent branching evolution with distinct mutational processes during early and late development. Metrics of genetic divergence between regions provided evidence of strong selection pressures during UPS development that further increased during radiotherapy. Subclone abundance changed after radiotherapy with subclone contraction tied to alterations in calcium signaling, and inhibiting calcium transporters radiosensitized sarcoma cells. Finally, circulating tumor DNA analysis accurately measured subclone abundance and enabled noninvasive monitoring of subclonal changes. These results demonstrate that radiation exerts selective pressures on UPSs and suggest that targeting radioresistant subclonal populations could improve outcomes after radiotherapy. Significance: Radiotherapy mediates tumor evolution by leading to the expansion of resistant subclonal cancer cell populations, indicating that developing approaches to target resistant subclones will be crucial to improve radiotherapy response.

In most solid tumors, cellular energy metabolism is primarily dominated by aerobic glycolysis, which fulfills the high demand for biomacromolecules at the expense of reduced ATP production efficiency. Elucidation of the mechanisms by which rapidly proliferating malignant cells acquire sufficient energy in this state of inefficient ATP production from glycolysis could enable the development of metabolism-targeted therapeutic strategies. In this study, we observed a significant association between elevated expression levels of the long noncoding RNA small nuclear RNA host gene 17 (SNHG17) and unfavorable prognosis in breast cancer. SNHG17 promoted breast cancer cell proliferation by augmenting mitochondrial ATP production. Mechanistically, SNHG17 directly interacted with the P65 subunit of NF-κB and phosphorylated P65 at the threonine 505 site. SNHG17 bound to P65 at its truncated loop2 site, recruited P65 to mitochondria, and coregulated the transcriptional activation of mitochondrial DNA to promote ATP production. Accordingly, targeting SNHG17 with an antisense oligonucleotide significantly reduced breast cancer tumor growth both in vitro and in vivo. Overall, these results established a role for SNHG17 in promoting breast cancer progression by increasing ATP production and provided insights into the reprogramming of energy metabolism in solid tumors. Significance: SNHG17 cooperates with NF-κB to induce expression of mitochondrial DNA and boost ATP production in breast cancer, suggesting that targeting SNHG17 could reverse metabolic reprogramming to suppress tumor progression.

Transgenic mice and organoid models, such as three-dimensional tumoroid cultures, have emerged as powerful tools for investigating cancer development and targeted therapies. Yet, the extent to which these preclinical models recapitulate the cellular identity of heterogeneous malignancies, like neuroblastoma, remains to be validated. In this study, we characterized the transcriptional landscape of TH-MYCN tumors by single-cell RNA sequencing and developed ex vivo tumoroids. Integrated analysis with murine fetal adrenal samples confirmed that both TH-MYCN tumors and tumoroids closely mirror the cellular profiles of normal embryonic sympathoblasts and chromaffin cells. Comprehensive comparison between tumors from patients with neuroblastoma and TH-MYCN mice demonstrated similarities in adrenergic tumor cell composition. Ex vivo tumoroid cultures displayed histologic resemblance and shared transcriptional profiles with the originating TH-MYCN tumors and human neuroblastoma tumors. Importantly, subpopulations within tumoroids exhibited gene expression associated with poor survival of patients with neuroblastoma. Notably, recurrent observations of a low-proliferative chromaffin phenotype connected to the highly proliferative sympathetic phenotype suggested that pushing sympathoblasts into a chromaffin-like state may offer an interesting therapeutic strategy for neuroblastoma. Together, this study not only deepens our understanding of a widely used transgenic mouse neuroblastoma model but also introduces an ex vivo model that maintains critical adrenergic cell state identity, thereby enhancing its translational potential for neuroblastoma research. Significance: Transgenic mouse models and ex vivo tumoroids, characterized through single-cell RNA sequencing, faithfully recapitulate neuroblastoma cellular identity, offering a useful platform for investigating potential therapeutic strategies.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super-enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as an SE-associated gene in human PDAC, which encodes the flavin monooxygenase enzyme that induces actin depolymerization and indirectly promotes serum response factor transcription by modulating the availability of serum response factor coactivators such as myocardin-related transcription factors (MRTF-A and MRTF-B). MICAL2 was overexpressed in PDAC, and high-MICAL2 expression correlated with poor patient prognosis. Transcriptional analysis revealed that MICAL2 upregulates KRAS and epithelial-mesenchymal transition signaling pathways, contributing to tumor growth and metastasis. In loss- and gain-of-function experiments in human and mouse PDAC cells, MICAL2 promoted both ERK1/2 and AKT activation. Consistent with its role in actin depolymerization and KRAS signaling, loss of MICAL2 also inhibited macropinocytosis. MICAL2, MRTF-A, and MRTF-B influenced PDAC cell proliferation and migration and promoted cell-cycle progression in vitro. Importantly, MICAL2 supported in vivo tumor growth and metastasis. Interestingly, MRTF-B, but not MRTF-A, phenocopied MICAL2-driven phenotypes in vivo. This study highlights the multiple ways in which MICAL2 affects PDAC biology and provides a foundation for future investigations into the potential of targeting MICAL2 for therapeutic intervention. Significance: Characterization of the epigenomic landscape of pancreatic cancer to identify early drivers of tumorigenesis uncovered MICAL2 as a super-enhancer-associated gene critical for tumor progression that represents a potential pharmacologic target.