We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived

Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic

Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON)

Effective therapies for pancreatic ductal adenocarcinoma (PDAC) have been largely elusive. Here, we perform Multiplexed kinase Inhibitor Bead Mass Spectrometry on 102 patient derived xenografts derived from 14 unique primary PDAC to define the tumor-intrinsic kinome landscape. Our findings uncover three kinome subgroups making up two tumor-intrinsic kinome subtypes that we call kinotypes. The kinotypes

Summary: This article discusses the specific advances made in precision oncology in 2024. We comment on the evolving nature of predictive molecular events used to select patients who will most benefit clinically from treatment. We also discuss advances in the development of strategic treatment regimens for combination therapies, rational drug design of small-molecule inhibitors, and structurally informed

Summary:Aneuploidy, an imbalance in chromosome number, is a hallmark of human cancers with chromosomal instability, and it remains a major therapeutic challenge. In this issue, Ippolito and colleagues identify RNA and protein turnover as targetable therapeutic vulnerabilities in aneuploid cancers.See related article by Ippolito et al., p. 2532

Summary:The study by Grossmann and colleagues uses single-nucleus RNA sequencing in a cohort of matched high-risk neuroblastoma primary tumor samples, obtained from the same patient at diagnosis and definitive surgery, to identify persister cells that survive induction chemotherapy. These persister cells utilize mechanisms of chemoresistance that are both tumor-intrinsic and tumor-extrinsic, are highly

Summary:In this issue, Klingbeil and colleagues deploy a paralog co-targeting strategy to reveal microtubule affinity–regulating kinases 2 and 3 as redundant negative regulators of the Hippo pathway and potentially actionable targets in YAP/TAZ-addicted tumors.See related article by Klingbeil et.al., p. 2471

Systematic multi-omics analysis revealed ancestry-dependent molecular alterations, but their impact on the efficacy of anti-cancer treatment is yet largely unknown. Here, we analyzed clinical trials from ClinicalTrials.gov and found that only 8,779/102,721 (8.5%) oncology clinical trials posted information on enrollment by race/ethnicity. The underrepresentation of non-White populations suggests that

Low intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogeneous tumors are variably aggressive, and the immunological factors impacting aggressiveness remain understudied. Here, we analyzed the mechanisms underlying immune escape in murine tumors with low ITH. We used immunophenotyping and single-cell RNA sequencing to compare

Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. Here, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ~800 cancer cell lines, nominating a poorly studied kinase

Hepatocellular carcinoma presents strong sexual dimorphism, being 2-3 times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic anti-tumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors

How cancer cells escape immune surveillance and resist immune checkpoint blockade (ICB) remains to be fully elucidated. By screening candidate genes frequently gained in cancer, we identified expression of ubiquitin-like modifier activating enzyme 1 (UBA1) as being the most negatively correlated with signatures related to effector CD8+ T-cells. High UBA1 expression was strongly predictive of treatment

Stem cells (SCs) and not progenitors (Ps) act as cells of origin of Basal Cell Carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumour development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis was preferentially expressed in SCs. Using

The vagal nerve is linked to tumorigenesis in multiple tissues including small cell lung cancer (SCLC). However, the role of sympathetic neuron in SCLC development remains unknown. Here, we observed a significant reduction in tumor growth following chemical denervation of local sympathetic nerves in a mouse model of SCLC. Further study identified that β2-adrenergic receptor (ADRB2) on cancer cells

Summary: Pharmacologically targeting tumor suppressors necessitates an unprecedented strategy of restoring, rather than conventionally inhibiting, protein function, and p53, the most commonly mutated protein in cancer, has thus remained undruggable. In this study, we address long-standing misconceptions in the field and gaps in the scientific logic for a p53 function–restoration strategy, identify

Summary: In this issue, Gainor and colleagues report on the immunogenicity of personalized neoantigen-encoding mRNA vaccines that elicit measurable polyfunctional CD8+ and CD4+ T-cell responses in patients whose tumors have been resected. Reactivity is substantiated to 20% to 30% of the predicted MHC-I and MHC-II epitopes in four patients with NSCLC postsurgically treated with the vaccine alone and

Summary: Gastric cancer remains one of the top cancers in China compared with Western countries, mainly attributed to the high rates of Helicobacter pylori infection. However, recent discoveries on the non–H. pylori gastric microbiome have led to a paradigm shift in our understanding of microbial risk factors driving gastric cancer, which will impact future screening and prevention strategies.

Summary: Despite an increasingly detailed understanding of cancer hallmarks at molecular or atomic resolution, most studies, however, fall short of investigating the systemic interactions of cancer with the human body. We propose to investigate the hallmarks of cancer from an organ-wide macroscopic view, discuss the challenges in preclinical and clinical research to study the cross-organ regulation

Summary: Current strategies for early cancer detection and diagnosis need updating to achieve greater precision, necessitating the creation of a comprehensive evolutionary map of tumorigenesis. This requires establishing high-quality prospective cohorts, systematically collecting samples for integrated spatiotemporal multiomics analyses, and efficiently translating laboratory findings into clinical

Summary: Traditional Chinese medicine has accumulated a wealth of experiences in individualized cancer prevention and serves as a complement to Western medicine. We propose an artificial intelligence–based integration of traditional and Western medicine as a new paradigm for cancer prevention, encompassing cancer risk screening and preventive intervention, which will provide new solutions for cancer

Summary: This commentary provides an in-depth exploration of the intricate relationships among diet, obesity, immune function, and cancer, highlighting the potential role of dietary interventions as complementary therapies in cancer treatment. Multiple analyses underscore the importance of personalized dietary strategies in cancer management and identify opportunities for further research in this evolving

Summary: In this issue, four articles highlight the critical role of nongenetic mechanisms and cell plasticity in mediating resistance to different classes of RAS inhibitors in pancreatic ductal adenocarcinoma and non–small cell lung cancer. See related article by Benitz et al., p. 2162 See related article by Dilly et al., p. 2135 See related article by Araujo et al., p. 2183 See related article by

Summary: The conventional wisdom is that the overwhelming majority of neoantigens arise from chromosomal DNA mutations; however, recent studies show that posttranscriptional and posttranslational events can also generate neoantigens. This commentary provides an overview of known and potential sources of nonchromosomal neoantigens, emerging technologies, and clinical trials that may move this field

Summary: Annual low-dose CT screening of individuals with a smoking history identifies early curable lung tumors and reduces cancer mortality by 20%, yet only a minority of eligible patients undergo such monitoring. Mazzone and colleagues apply a blood-based cfDNA fragmentomic assay as a high-sensitivity/low-specificity pre-screen to help stratify individuals who may benefit most from more definitive

Summary: Significant efforts have been made to identify and validate oncoproteins and ncRNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements, which orchestrate the 3D organization of the genome and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts

Summary: The Chinese government has, in recent decades, implemented various administrative laws and regulatory policies to expedite cancer therapeutic development, boosting research and development pipelines for domestic pharmaceutical companies and clinical trials; however, China faces unique challenges given the high prevalence of certain cancer types and distinct disease burdens, some of which are

Precision oncology tailors treatment strategies to a patient’s molecular and health data. Despite the essential clinical value of current diagnostic methods, hematoxylin and eosin morphology, immunohistochemistry, and gene panel sequencing offer an incomplete characterization. In contrast, highly multiplexed tissue imaging allows spatial analysis of dozens of markers at single-cell resolution enabling

Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head

Cancer is pervasive across multicellular species, but what explains the differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades of tetrapods (amphibians, sauropsids, and mammals), we found that neoplasia and malignancy prevalence increases with adult mass (contrary to Peto’s paradox) and somatic mutation rate but decreases with gestation

Antibody–drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into

The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation

Glioblastoma is characterized by heterogeneous malignant cells that are functionally integrated within the neuroglial microenvironment. Here, we model this ecosystem by growing glioblastoma into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex. Single-cell RNA-seq analysis suggests that, compared to matched gliomasphere models, glioblastoma

Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, “nonmutational epigenetic reprogramming” was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and

Summary: For more than three decades, concurrent advances in laboratory technologies and computer science have driven the rise of cancer informatics. Today, software tools for cancer research are indispensable to the entire cancer research enterprise.

Summary: People diagnosed with cancer and their formal and informal caregivers are increasingly faced with a deluge of complex information, thanks to rapid advancements in the type and volume of diagnostic, prognostic, and treatment data. This commentary discusses the opportunities and challenges that the society faces as we integrate large volumes of data into regular cancer care.

Summary: In this issue, Waarts and colleagues developed an advanced ex vivo CRISPR screening platform to identify vulnerabilities in clonal hematopoiesis (CH). This unique system allowed the authors to identify a link between IDH2 and TET2 CH mutations, histone demethylases, and altered cytokine signaling, which enabled targeting by ruxolitinib leading to the elimination of CH clones, offering a possible

Summary: Baker and colleagues developed a new algorithm called “Gain Route Identification and Timing In Cancer” (GRITIC) to uncover the path of chromosomal evolution in a tumor, particularly in the context of whole-genome duplication. Their approach found that tumors with genome doubling frequently take an indirect path from one copy number state to another. In addition, the timing of genome doubling

Summary: Ameliorating the tumor immune microenvironment is a key strategy to improve the therapeutic outcomes of patients with cancer. Sandoval and colleagues demonstrate that iron chelation enhances type I IFN production, promotes NK cell tumor trafficking and activation, and synergizes with chemotherapy drug cisplatin to reduce metastatic ovarian cancer progression in murine models. See related article

Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor

Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived

Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global "hub-and-spoke" network model to expand access to and accelerate clinical trials

Patients with head and neck squamous cell carcinomas (HNSCC) often have poor outcomes due to suboptimal risk-management and treatment strategies; yet integrating novel prognostic biomarkers into clinical practice is challenging. Here, we report the presence of multinucleated giant cells (MGC) – a type of macrophages – in tumors from patients with HNSCC, which are associated with a favorable prognosis

Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested.

Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden

Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively

Summary: Polatuzumab vedotin, an antibody–drug conjugate targeting CD79B, is the first new drug approved for first-line therapy of diffuse large B-cell lymphoma in more than two decades, although factors determining treatment responses to polatuzumab vedotin remain unknown. Two new studies identified central mechanisms of lower sensitivity, namely reduced accessibility of the CD79B epitope through

Summary: There is no general consensus on the set of mutations capable of driving the age-related clonal expansions in hematopoietic stem cells known as clonal hematopoiesis, and current variant classifications typically rely on rules derived from expert knowledge. In this issue of Cancer Discovery, Damajo and colleagues trained and validated machine learning models without prior knowledge of clonal

Summary: Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism

TET2 mutations (mTET2) are common genetic events in myeloid malignancies and clonal hematopoiesis (CH). These mutations arise in the founding clone and are implicated in many clinical sequelae associated with oncogenic feedforward inflammatory circuits. However, the direct downstream effector of mTET2 responsible for the potentiation of this inflammatory circuit is unknown. To address this, we performed

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here we performed detailed clinicopathologic, genomic and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis