Highlighted Research Articles

Cai and colleagues infused 13C-glucose into patients undergoing resection of non–small cell lung cancer (NSCLC), then followed the patients for several years. This allowed the authors to identify 13C labeling features that correlated with outcomes. Among all metabolic features analyzed, 13C labeling in tumor-derived tricarboxylic acid (TCA) cycle metabolites best predicted early recurrence and death. Because most patients died with metastasis, the authors used patient-derived NSCLC xenografts to explore the connection between TCA cycle labeling and metastasis. Their findings suggest that inhibiting the electron transport chain reduces both TCA cycle labeling and metastasis, without impacting tumor growth at the site of implantation.See article, p. 702.George and colleagues profiled a large heterogenous cohort of matched diagnostic–relapse tumor tissue and paired plasma-derived cell-free DNA (cfDNA) from patients with relapsed solid tumors of childhood. Serial tumor sequencing identified putative drivers of relapse. A higher degree of intratumor heterogeneity was captured by cfDNA sequencing compared with tumor sequencing, if sufficient circulating tumor-derived DNA was present. Fragmentomic analysis of cfDNA identified tumor-specific transcription factor binding sites accessible in chromatin. This study identifies genomic and epigenetic drivers of childhood cancer relapse and highlights the power of cfDNA analysis to capture intratumoral heterogeneity and the epigenetic state of cancer cells.See article, p. 717.Patients with large B cell lymphoma (LBCL) who progress after anti-CD19 CAR T-cell therapy (CAR19) may benefit from subsequent anti-CD22 CAR T-cell therapy (CAR22). Su and colleagues found that the number of residual CAR19 cells remained minimal at the time of CAR22 infusion. CAR19 cells had negligible expansion and did not impact CAR22 efficacy, toxicity, or expansion. Interestingly, patients who underwent leukapheresis for CAR22 more than 6 months after CAR19 had more favorable T-cell phenotypes, such as higher CD4+ naïve T and CD4+/CD8+ T-central memory cells, with lower CD4+ T-effector memory cells. Importantly, a higher proportion of central memory T cells in the CAR22 product was associated with better clinical outcomes.See article, p. 733.Patients undergoing hematopoietic cell transplants receive intense conditioning treatments that cause severe cytopenias. Nishino and colleagues found that non-selective β-blockers, but not β1-selective inhibitors, impaired hematopoietic regeneration after hematopoietic cell transplants in mice and humans. Patients who underwent transplants at UT Southwestern and Vanderbilt and received non-selective β-blockers exhibited prolonged cytopenias and worse survival. These effects were most pronounced in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis. This suggests that holding non-selective β-blockers or replacing with β1-selective inhibitors after transplantation can shorten the duration of cytopenias and improve clinical outcomes.See article, p. 748.Ma and colleagues mapped the intricacies of cellular ecosystems in gastric tumors, revealing unprecedented insights into tumor heterogeneity and evolution. Integrating spatial transcriptomics with single-cell expression profiles from 121 patients, the study uncovered distinct evolutionary trajectories and ecosystem states associated with specific molecular subtypes and clinical outcomes. Computational analysis highlighted the role of tumor–stromal interfaces associated with markers such as increased GREM1 expression. This comprehensive mapping of cellular ecosystems within gastric cancer provides a deeper understanding of how tumors are shaped by both intrinsic and extrinsic factors, paving the way for more personalized treatment approaches in gastric cancer.See article, p. 767.Subsets of transcribed repetitive elements are capable of inducing “viral mimicry” responses to promote adaptive immune responses against an affected cell. Paradoxically, cancer-initiating events also promote the transcription of immunostimulatory repetitive elements capable of inducing viral mimicry responses. Ishak and colleagues explored this paradox and discovered that chronic agonism of cytosolic nucleic acid sensing by transcribed repetitive elements selected for the acquisition of immune evasion properties, thus implicating transcribed repetitive elements in the acquisition of cancer hallmarks. Pharmacologic attenuation of this “viral mimicry conditioning” process offers an opportunity to interrupt the acquisition of these pro-tumorigenic phenotypes.See article, p. 793.Enhancing therapeutic strategies to impede metastatic expansion remains an unmet need. Alam and colleagues uncovered a bone-mediated mechanism that enriches the pool of HER2-expressing circulating tumor cells (CTCs) in patients with initial HR+/HER2− breast cancer. They revealed osteoblast-mediated miRNA-regulatory effects on HER2 expression and identified a new NRG3/mTOR autocrine axis that reduced the tumor microenvironment (TME) dependency of disseminated tumor cells while enhancing their metastasis seeding ability. Blocking this axis impeded secondary metastasis to visceral organs. In addition to informing clinical strategies for early diagnosis and treatment of bone metastasis in HR+/HER2− breast cancer, this study underscores the role of HER2 phenotypic mimicry in metastatic spread and switch in organotropism.See article, p. 818.The role of ubiquitin-mediated mechanisms in the regulation of germinal center B-cell development and B-cell lymphomagenesis are poorly understood. Sahasrabuddhe and colleagues identified a haploinsufficient tumor suppressor function for FBXO45 in germinal center B cells and credentialed FBXO45 as a substrate-specific adaptor that targets GEF-H1 for ubiquitin-mediated proteasomal degradation. Conditional genetic ablation of Fbxo45 in transgenic mice resulted in abnormal expansion of the germinal center B-cell compartment and highly penetrant B-cell lymphomagenesis. Fbxo45-deficient tumors accumulated GEF-H1 and exhibited prolonged activation of the MAPK pathway with increased sensitivity to MEK inhibitors, implicating a therapeutic strategy for FBXO45-deficient lymphomas.See article, p. 838.