{
  "abstract": "Background Clear cell renal cell carcinoma (ccRCC) exhibits significant heterogeneity due to morphological changes and tumor microenvironment dynamics, influencing systemic therapy responses. While the role of high-mobility group AT-hook 2 (HMGA2) in tumor progression has been implicated in other cancers, its significance in ccRCC remains unclear. This study investigates the role of HMGA2 in these processes and its clinical impact.Methods Spatial transcriptomics (ST) was performed on primary ccRCC samples to investigate expression trajectories associated with HMGA2 expression and morphological evolution. In metastatic ccRCC cohorts treated with systemic therapy, immunohistochemistry and bulk RNA sequencing data were analyzed to evaluate molecular and clinical features in relation to HMGA2. Single-cell RNA sequencing (scRNA-seq) data were used to explore immune cell populations and their interactions. Based on these findings, multiplex immunohistochemistry (mIHC) assessed spatial distribution, cell–cell interactions, and pathological responses of key immune populations.Results HMGA2 expression was associated with aggressive morphological patterns, such as solid sheets and rhabdoid/sarcomatoid. ST revealed a progressive increase in HMGA2 expression along the morphological trajectory, marked by a shift from clear to eosinophilic cytoplasm, with eccentric nuclei and prominent nucleoli, and loss of vascular architecture. HMGA2-high tumors exhibited aggressive phenotypes driven by cell cycle, epithelial-mesenchymal transition, and inflammatory signaling pathways. Clinically, patients with high HMGA2 had worse progression-free survival but responded better to immune checkpoint inhibitor combination (Combo-ICI) therapy than to tyrosine kinase inhibitor monotherapy. To assess the immune landscape, scRNA-seq data revealed that HMGA2-high tumors were enriched with progenitor exhausted CD8+ T cells (Tpex), along with increased frequencies of conventional dendritic cell type 1 (cDC1) and inflammatory cDC type 2, which were found to interact with Tpex via ICAM-1. mIHC confirmed that Tpex were enriched among Combo-ICI responders in HMGA2-high tumors, with higher densities and closer proximity to ICAM-1+ cDC1.Conclusions These findings suggest that dynamic HMGA2 expression contributes to morphological evolution and modulates immune responses through enhanced Tpex–cDCs engagement, serving as a potential marker for systemic therapy response in ccRCC. However, additional experimental studies are required to validate these mechanisms.",
  "authors": [
    {
      "affiliations": [
        "Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan",
        "Department of Pathology, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Takahiro Nakamoto"
    },
    {
      "affiliations": [
        "Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan",
        "Department of Urology, Osakafu Saiseikai Noe Hospital, Osaka, Osaka, Japan"
      ],
      "name": "Takashi Yoshida"
    },
    {
      "affiliations": [
        "Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan",
        "Department of Surgical Pathology, Hyogo Medical University, Nishinomiya, Hyogo, Japan"
      ],
      "name": "Chisato Ohe"
    },
    {
      "affiliations": [
        "Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Yoshiki Yasukochi"
    },
    {
      "affiliations": [
        "Department of Pathology, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Naho Atsumi"
    },
    {
      "affiliations": [
        "Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Takeshi Sano"
    },
    {
      "affiliations": [
        "Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Koichiro Higasa"
    },
    {
      "affiliations": [
        "Department of Pathology, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Katsunori Uchida"
    },
    {
      "affiliations": [
        "Department of Pathology, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Koji Tsuta"
    },
    {
      "affiliations": [
        "Department of Urology and Andrology, Kansai Medical University, Hirakata, Osaka, Japan"
      ],
      "name": "Hidefumi Kinoshita"
    }
  ],
  "title": "HMGA2 links morphological evolution and microenvironment dynamics to systemic therapy response in clear cell renal cell carcinoma",
  "uid": "45c0bea1-14a3-52e3-a864-bb08c8cc1c80"
}