Cancer Communications最新文献

The cover image is based on the article Intranuclear paraspeckle-circular RNA TACC3 assembly forms RNA-DNA hybrids to facilitate MASH-related hepatocellular carcinoma growth in an m⁶A-dependent manner by Hongyang Wang et al., https://doi.org/10.1002/cac2.70061.

The cover image is based on the article CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer by Jiaqi Liang et al., https://doi.org/10.1002/cac2.70068.

Background: The prognosis for non-small cell lung cancer (NSCLC) patients with extensive brain metastases (BMs) treated with radiotherapy alone remains poor. Based on the synergistic potential of radiotherapy and angiogenesis inhibitors, we initiated this phase II study to assess the efficacy and safety of combining bevacizumab (Bev) with fractionated stereotactic radiotherapy (FSRT) in managing extensive BMs in NSCLC patients who had stable extracranial disease.

Methods: Patients with extensive BMs from NSCLC, deemed unsuitable for stereotactic radiosurgery, were prospectively enrolled following multidisciplinary tumor board evaluation. Patients received FSRT (40 Gy in 10 fractions or 30 Gy in 5 fractions) in combination with Bev (7.5 mg/kg on day 1 prior to FSRT and on day 21 post-FSRT). The primary endpoint was intracranial progression-free survival (IPFS). Secondary endpoints included overall survival, progression-free survival, quality of life (QOL), and toxicities. For comparison, NSCLC patients with extensive BMs treated with whole-brain radiotherapy (WBRT) plus FSRT or FSRT alone were matched 1:1 with the study group (Bev + FSRT) using the propensity score matching.

Results: One hundred and six patients were included in the Bev + FSRT group, with a median follow-up duration of 35.8 months. The median IPFS was 18.3 months (95% confidence interval, 15.2-23.3 months). The Bev + FSRT group showed a significant improvement in IPFS compared to both the WBRT + FSRT group (9.6 months, P < 0.001) and the FSRT alone group (8.9 months, P < 0.001). Treatment was well tolerated, with grade 1 radiation necrosis in 1 patient. Bev + FSRT treatment significantly reduced tumor volume (P < 0.001), peritumoral edema volume (P = 0.004), and vascular leakage (P < 0.001). Furthermore, QOL was significantly improved after Bev + FSRT treatment, particularly in patients with symptomatic extensive BMs.

Conclusion: These findings support the combination of Bev and FSRT as a safe and effective treatment strategy for extensive BMs in NSCLC patients, offering improved intracranial disease control and symptom relief while avoiding the neurotoxicity associated with WBRT. A randomized trial is warranted to validate the findings of the current study.

Trial registration: ClinicalTrials.gov, NCT04345146. Registration date: 2020-02-22.

Background: Metastasis is the leading cause of cancer-related mortality, with circulating tumor cell (CTC) clusters serving as highly efficient precursors of distant metastasis. Survival of CTC clusters in the bloodstream is the primary contributor to tumor metastasis. However, the underlying mechanisms of how CTC clusters respond to the blood environment and drive metastasis remain elusive. This study aimed to elucidate the potential mechanisms that enable CTC clusters to adapt and survive in the bloodstream.

Methods: CTC clusters were detected using a microfluidic system in cancer patients, as well as in patient-derived xenograft (PDX), cell line-derived xenograft, and syngeneic models. The key molecules responsible for the adaptive survival of CTC clusters were characterized using RNA-sequencing (RNA-seq), gene interference, and flow cytometry. To investigate the underlying mechanisms of adaptive survival, RNA-seq, targeted metabolomics, isotope tracing experiments, chromatin immunoprecipitation (ChIP) sequencing, and immunofluorescence (IF) staining were employed. The therapeutic potential of survival pathway inhibitor combined with chemotherapy drug was evaluated in patient-derived CTCs and the PDX model.

Results: CTC clusters exhibited superior survival and metastatic capacity compared to single CTCs and were associated with adverse clinical outcomes. The unfolded protein response mediator protein kinase R-like endoplasmic reticulum kinase (PERK) was activated in CTC clusters and maintained S-adenosylmethionine (SAM) availability, facilitating their adaptive survival in the bloodstream. Mechanistically, PERK mediated the upregulation of activating transcription factor 4 (ATF4), which enhanced methionine adenosyltransferase 2A (MAT2A) expression, contributing to SAM synthesis. Increased SAM enhanced H3K4me3 modification of the platelet-derived growth factor B (PDGFB) promoter, leading to elevated PDGFB secretion and its accumulation in the intercellular region within CTC clusters. PDGFB functioned as a shared survival signal, triggering the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway via platelet-derived growth factor receptor beta (PDGFRβ), supporting CTC cluster survival in the bloodstream. Inhibition of PERK and PDGFRβ profoundly impaired the survival signaling and suppressed the metastatic dissemination of CTC clusters.

Conclusions: Our findings revealed a PERK/MAT2A/PDGFB axis that confers adaptive survival capabilities to CTC clusters in the bloodstream. Targeting this survival signaling pathway represents a promising therapeutic strategy for metastatic cancer.

Background: Brain metastasis, a leading cause of death in patients with lung adenocarcinoma (LUAD), arises from tumor cells adapting to the unique microenvironment of the brain through metabolic remodeling regulated by key oncogenes. Here, we aimed to determine the role of high mobility group protein box 3 (HMGB3) in regulating tumor cell metabolism to promote the progression and brain metastasis of LUAD.

Methods: A LUAD cell model predisposed to brain metastasis was established, followed by differential gene expression analysis. HMGB3 expression was quantified via single-cell RNA sequencing (scRNA-seq) and immunohistochemistry, with clinical relevance assessed in two retrospective cohorts: the primary LUAD and the LUAD brain metastasis cohorts. Gene enrichment analysis of scRNA-seq and bulk RNA-seq data, along with Western blotting, were performed to identify HMGB3-associated pathways. Co-immunoprecipitation combined with mass spectrometry was used to detect HMGB3-interacting proteins. Gain-of-function, loss-of-function and rescue experiments targeting HMGB3 downstream pathways were conducted in vitro and in vivo.

Results: HMGB3 expression was significantly elevated in both primary LUAD lesions and brain metastatic foci, and its upregulation was strongly associated with poor prognosis in LUAD patients, as well as in those with concomitant brain metastasis. HMGB3 enhanced the migration, invasion, and epithelial-mesenchymal transition (EMT) capabilities of LUAD cells in vitro and promoted the development of brain metastasis in vivo. Mechanistically, HMGB3 recruited and interacted with single-stranded DNA-binding protein 1 (SSBP1), inducing its nuclear translocation and reprogramming mitochondrial metabolism. This process elevated cytoplasmic reactive oxygen species levels, which subsequently activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway through downregulating phosphatase and tensin homolog (PTEN), ultimately promoting tumor cell proliferation, migration, invasion, and EMT.

Conclusions: This study demonstrated HMGB3 as a key regulator of the brain metastasis of LUAD, orchestrating tumor cells' metabolic adaptation to the brain microenvironment through modulation of mitochondrial metabolism, thereby offering potential therapeutic targets for LUAD brain metastases.