bims-tumhet Biomed News
on Tumor heterogeneity
Issue of 2025–05–11
three papers selected by
Sergio Marchini, Humanitas Research
  1. The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.
  2. Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.
  3. Multi-cancer early detection via a DNA methylation multiplex ddPCR-based blood test.
  1. Nat Cancer. 2025 May 08.
    The Curated Cancer Cell Atlas provides a comprehensive characterization of tumors at single-cell resolution.
    Michael Tyler, Avishai Gavish, Chaya Barbolin, Roi Tschernichovsky, Rouven Hoefflin, Michael Mints, Sidharth V Puram, Itay Tirosh.
      Recent years have seen a rapid proliferation of single-cell cancer studies, yet most of these studies profiled few tumors, limiting their statistical power. Combining data and results across studies holds great promise but also involves various challenges. We recently began to address these challenges by curating a large collection of cancer single-cell RNA-sequencing datasets, leveraging it for systematic analyses of tumor heterogeneity. Here we greatly extend this repository to 124 datasets for over 40 cancer types, together comprising 2,836 samples, with improved data annotations, visualizations and exploration. Using this vast cohort, we generate an updated map of recurrent expression programs in malignant cells and systematically quantify context-dependent gene expression and cell-cycle patterns across cell types and cancer types. These data, annotations and analysis results are all freely available for exploration and download through the Curated Cancer Cell Atlas, a central community resource that opens new avenues in cancer research.
    DOI:  https://doi.org/10.1038/s43018-025-00957-8
  2. Genes Dev. 2025 May 05.
    Aneuploidy generates enhanced nucleotide dependency and sensitivity to metabolic perturbation.
    Rayna Y Magesh, Arshia N Kaur, Faith N Keller, Abdulrazak Frederick, Tenzin Tseyang, John A Haley, Alejandra M Rivera-Nieves, Anthony C Liang, David A Guertin, Jessica B Spinelli, Stephen J Elledge, Emma V Watson.
      Despite the general detriment of aneuploidy to cellular fitness, >90% of solid tumors carry an imbalanced karyotype. This existing paradox and the molecular responses to aneuploidy remain poorly understood. Here, we explore these cellular stresses and unique vulnerabilities of aneuploidy in human mammary epithelial cells (HMECs) enriched for breast cancer-associated copy number alterations (CNAs). To uncover the genetic dependencies specific to aneuploid cells, we conducted a comprehensive, genome-wide CRISPR knockout screen in isogenic aneuploid and diploid HMEC lines. Our study reveals that aneuploid HMECs exhibit an increased reliance on pyrimidine biosynthesis and mitochondrial oxidative phosphorylation genes and demonstrate heightened fitness advantages upon loss of tumor suppressor genes. Using an integrative multiomic analysis, we confirmed nucleotide pool insufficiency as a key contributor to widespread cellular dysfunction in aneuploid HMECs with net copy number gain. Although diploid cells can switch seamlessly between pyrimidine synthesis and salvage, cells with increased chromosomal content exhibit p53 activation and S-phase arrest when relying on salvage alone, alongside increased sensitivity to DNA-damaging chemotherapeutics. This work advances our understanding of the consequences of aneuploidy and uncovers potential avenues for patient stratification and therapeutic intervention based on tumor ploidy.
    Keywords:  CRISPR; aneuploidy; cancer; genomics; metabolism
    DOI:  https://doi.org/10.1101/gad.352512.124
  3. Int J Cancer. 2025 May 02.
    Multi-cancer early detection via a DNA methylation multiplex ddPCR-based blood test.
    Tiago Brito-Rocha, Vera Constâncio, Pedro Leite-Silva, Carina Carvalho-Maia, José Pedro Sequeira, Sofia Salta, João Lobo, Diana Inês Machado, Sandra P Nunes, Rui Silva-Santos, Rui Freitas, Carlos Gonçalves Dias, Cláudia Vieira, Marta Soares, Rui Henrique, Carmen Jerónimo.
      Early cancer detection through minimally invasive methods is key for improving patient outcomes. We aimed to assess the performance of a novel blood-based test leveraging DNA methylation patterns for simultaneous detection of lung (LC), breast (BrC), colorectal (CRC), and prostate (PCa) cancer. Using The Cancer Genome Atlas (TCGA) methylation data, we identified shared hypermethylated gene promoters (ADCY4, MIR129-2, NID2, and MAGI2) among those four cancers. Validation was performed using online datasets, an in-house tissue set (N = 179), and plasma samples (N = 485) using droplet digital PCR (ddPCR). The test showed sensitivities of 81.82% (lung), 45% (breast), 69.23% (colorectal), and 44.14% (prostate), with 91.04% specificity. Overall, the PanCancer panel achieved 60.1% sensitivity and 87.4% specificity in detecting these four cancers. In early-stage cancers, sensitivities were slightly lower but followed a similar trend. Additionally, the test detected nine other cancer types in plasma. This proof-of-concept study demonstrates the feasibility of a single methylation-targeted blood test for multi-cancer detection, offering potential as an affordable and scalable screening tool for early cancer detection.
    Keywords:  DNA methylation; epigenetics; liquid biopsy; multi‐cancer detection; screening
    DOI:  https://doi.org/10.1002/ijc.35467
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