{
  "abstract": "Background Ovarian cancer is the most lethal gynecologic malignancy worldwide, yet factors leading to therapy resistance are poorly understood, partly hindered by the heterogeneous tumor microenvironment (TME) and cancer phenotypes. This study aims to construct a single-cell atlas of epithelial ovarian cancer, to comprehensively characterize the TME ecotypes and cancer phenotypic states across the disease spectrum, thereby identifying mechanisms related to chemotherapy resistance and providing insights for more effective individualized therapies.Methods A total of 394 samples profiled with single-cell RNA sequencing were collected. Following data integration and unsupervised clustering, TME cell states were identified. Subsequently, immune ecotypes were defined based on samples with intact CD45 + compartments. Non-negative matrix factorization was performed on tumor cells to identify cancer metaprograms. The association of immune ecotypes, stromal subsets, and cancer metaprograms and their correlation with clinical parameters were dissected. Additionally, external spatial datasets were applied for validations.Results A total of 89 different TME cell types and states were identified, including 33 T/NK, 15 B/plasma, 18 myeloid, and 23 stromal cell types and states. These TME cells showed distinct distribution patterns among samples of different pathological types, stages, metastatic sites, and treatment statuses. Subsequently, based on the abundance of immune cell subsets, samples were categorized into six immune ecotypes, including naïve-like lymphocytes-enriched (Ecotype 1), primary tumor-enriched (Ecotype 2), metastatic tumor-enriched (Ecotype 3), post-chemotherapy-enriched (Ecotype 4), stress response (Ecotype 5), and immune-suppressive (Ecotype 6). Analysis of the cancer cell compartment led to identification of ten distinct ovarian cancer metaprograms, including antigen presentation, cell cycle, stress response, classical, partial epithelial-mesenchymal transition, interferon response, ciliary-like, inflammatory, hypoxia and angiogenesis, as well as ribosome and protein synthesis. Strong associations among immune ecotypes, stromal subsets, and cancer cell states were observed. Specifically, cancer cells expressing the classical metaprogram was highly enriched in chemotherapy non-responders, and co-localize with immune ecotypes 2, 3 and 6, along with multiple types of cancer-associated fibroblasts. Validations in independent spatial transcriptomic datasets of ovarian cancer indicate that the classical metaprogram was progressively upregulated during the course of chemotherapy, and highly enriched in minimal residual disease.Conclusions In summary, this study provided a comprehensive single-cell landscape of epithelial ovarian cancer, highlighting the heterogeneity of TME and cancer phenotypic states across patients. A cancer metaprogram related to chemotherapy response were identified, which may serve as novel predictive biomarkers and provide basis for developing therapeutics targeting chemo-resistant diseases.",
  "authors": [
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Yibo Dai"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Enyu Dai"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Yunhe Liu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Guangsheng Pei"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Kyung Serk Cho"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Minghao Dang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Jiahui Jiang"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Yang Liu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Anne Knisely"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Helen Clark"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Sanghoon Lee"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Idania Lubo"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Wei Lu"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Barrett Craig Lawson"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Luisa M Solis Soto"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Amir A Jazaeri"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Linghua Wang"
    }
  ],
  "title": "1246 A single-cell atlas of ovarian cancer reveals tumor microenvironmental heterogeneity and cancer cell plasticity in response to therapies",
  "uid": "1d7dd697-ff7b-5cab-b108-8808e9a576ac"
}