Highlighted Research Articles

Up to one-third of children who develop the childhood kidney cancer, Wilms tumor, carry a predisposition. Treger and colleagues examined the precise sequence of genetic events that lead from predisposition to tumor formation, utilizing whole-genome sequencing supplemented with RNA sequencing and genome-wide methylation readouts. The key finding was that some predisposition mutations greatly constrained genetic tumor evolution, as reflected, for example, in the development of the exact same configuration of somatic driver events. These findings suggest that Wilms tumors may require different treatment strategies depending on the underlying predisposition mutation.See article, p. 286.The glioblastoma tumor microenvironment is complex and heterogeneous, presenting a long-standing challenge for faithful in vitro tumor modeling. In this study, Mangena and colleagues characterized glioblastoma-cortical organoids (GCO), an in vitro glioblastoma model established by allografting patient-derived tumor cells into cellularly diverse human cortical organoids. GCOs recreated important aspects of malignant cell heterogeneity, supporting the faithfulness of these models. Moreover, the authors observed widespread transfer of malignant mRNAs to surrounding non-malignant cells, with a bias towards functionally defined cell populations. This transfer is mediated by extracellular vesicles, suggesting a possibly conserved communication mechanism that may extend to other cancers.See article, p. 299.Medullary thyroid carcinoma (MTC) is a difficult type of thyroid cancer that poses challenges in identifying metastatic lesions. In this study, Kong and colleagues utilized their previously developed fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) in localizing MTC lesions, and demonstrated an improved patient-based detection rate (98%), tumor uptake (SUVmax 11.71 ± 9.16), and pathology-validated diagnostic accuracy (96.7%) compared to the currently approved method. It directly altered management in 32% of patients and modified surgical plan in 66.7% of patients, enabling precision management of MTC.See article, p. 316.Pancreatic cancer is known for its aggressive growth characteristics, yet some pancreatic tumors have more indolent clinical features. To understand these differences, Mullen and colleagues quantified the evolutionary features of 91 pancreatic cancers representing the full spectrum of clinical presentations of this disease. They found that high truncal density, a metric of the accumulation of somatic mutations in the most recent common ancestor, was significantly associated with worse overall survival. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs were more likely to develop from locally advanced disease and had lower fractional allelic loss and increased likelihood of being monoclonal. These findings reveal the potential of incorporating evolutionary metrics into pancreatic cancer management.See article, p. 329.In this study, Xu and colleagues define the tumor-intrinsic kinome landscape of PDAC, uncovering distinct kinotypes that align with previously described molecular subtypes. Basal-like tumors, which make up about 20% of PDAC cases, show significant enrichment in receptor tyrosine kinases, including EGFR. Reexamining prior trials using EGFR inhibitors, this study found that patients with basal-like tumors responded better to small molecule inhibitors of EGFR compared to patients with classical tumors. To date, basal-like tumors have been shown to be more aggressive and chemoresistant. These findings provide a framework for subtype-specific targeted approaches and highlight the importance of precision oncology trials.See article, p. 346.Bao and colleagues propose the UBA1−STUB1 axis as a critical element in cancer immune evasion and resistance to immune checkpoint blockade (ICB). Elevated UBA1 expression correlated with poor outcomes in ICB-treated patients. Mechanistically, UBA1–STUB1 promoted degradation of JAK1, weakening interferon signaling and immune activation. Inhibition of UBA1 with the small molecule inhibitor TAK-243 enhanced antitumor immunity, increased functional CD8+ T cell infiltration, and synergized with ICB in preclinical models. These findings nominate UBA1 as a therapeutic target to improve ICB efficacy and advocate for its clinical evaluation in combination therapies.See article, p. 363.Fibrolamellar carcinoma (FLC) is a liver cancer of young individuals, characterized by oncogenic PKA fusions. Gritti and colleagues established that the central mechanism by which PKA fusions drive growth of FLC models is via phosphorylating and inhibiting salt-inducible kinases (SIK). The resulting stimulation of the CRTC2 transcriptional co-activator and its binding partner, the p300 histone acetyltransferase, factors normally negatively regulated by SIKs, promoted tumorigenesis. In patient samples, the SIK–CRTC2-regulated transcriptional signature distinguished FLC from other liver cancers, highlighting the role of the pathway in disease pathogenesis. Thus, targeting PKA or CRTC/p300 or activating SIK may represent potential therapeutic approaches for FLC.See article, p. 382.In this study, Bischoff and colleagues uncover copper’s (Cu) critical role in the progression of clear cell renal cell carcinoma (ccRCC). Advanced ccRCC was shown to accumulate Cu, which enhanced cytochrome c oxidase activity for mitochondrial respiration. Using multiomics, flux analysis, and genetic and pharmacologic tools, this investigation found that Cu boosted bioenergetics, biosynthesis, and detoxification to promote tumor growth. Single-cell and spatial transcriptomic analyses revealed a shift towards oxidative metabolism, altered glutathione and Cu pathways, and reduced HIF activity. Targeting Cu-driven metabolic remodeling offers potential for novel therapeutic strategies.See article, p. 401.Basal cell carcinoma (BCC) is the most frequent cancer in humans. Stem cells (SC), but not progenitor cells, are competent to initiate BCC formation following oncogenic Hedgehog signaling. The mechanisms that confer the competence of stem cells to initiate BCC are not known. Canato and colleagues uncover that Survivin, a protein regulating proliferation and apoptosis, is preferentially expressed by SCs. Genetic gain- and loss-of-function experiments demonstrated the importance of Survivin to license SC to form BCC by promoting self-renewal and restricting apoptosis and differentiation of oncogene-targeted SCs. These findings uncover mechanisms that allow SCs to give rise to BCC.See article, p. 427.