{
  "abstract": "Osteosarcoma progression involves complex spatiotemporal dynamics, yet the lineage relationships underlying tumor cell fate decisions remain poorly understood. Here we integrate single cell and spatial transcriptomics and mitochondrial variants-based lineage tracing to map the evolution of a late-stage, non-metastatic osteosarcoma. Single cell pseudotemporal reconstruction of malignant cells reveals a stepwise cascade of transcriptional programs that are associated with bifurcation of COL3A1+ progenitors into ALPL+ osteoblastic and THY+ mesenchymal lineages. Critically, we demonstrate that the metastatic THY1+ mesenchymal cell fate is not governed by cell-autonomous transcriptional programs alone; this pro-tumorigenic state is associated with spatial co-localization with PLVAP+ dysfunctional endothelia to form a pro-metastatic niche (THY1_Endo) enriched for PTN/NOTCH signaling. To distinguish clonal ancestry from microenvironmental plasticity, we leveraged spatially resolved somatic mitochondrial variants as endogenous lineage tracers. A spatial autocorrelation filter confirmed significant clonal spatial coherence (Z = 10.07, p {approx} 4 x 10-24). Phylogenetic reconstruction using a Wright-Fisher drift model coupled with a hidden Markov tree (WF-HMT) identified COL3A1+ cells as the ancestral tumour state with ALPL+ and THY1+ states acquired repeatedly and independently across the phylogeny. We propose a \"time-space-lineage\" relay model where sequential microenvironmental signals are associated with tumor cell fate and pre-metastatic niche assembly through clonal commitment. This multi dimensional framework bridges single cell states, spatial organization, temporal dynamics, and clonal ancestry - underscoring the power of somatic mitochondrial variants to resolve clonal history and intercept cancer evolution.",
  "abstract_shown": true,
  "affiliations": [
    "The University of Hong Kong"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "Y. Xue"
    },
    {
      "name": "Z. Su"
    },
    {
      "name": "J. Su"
    },
    {
      "name": "A. S. Chu"
    },
    {
      "name": "H. Yu"
    },
    {
      "name": "L. Wan"
    },
    {
      "name": "M. Chen"
    },
    {
      "name": "Y. Lin"
    },
    {
      "name": "J. P. Y. Cheung"
    },
    {
      "name": "K. S. C. Cheung"
    },
    {
      "affs": [
        0
      ],
      "name": "J. W. K. Ho"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3t6rqegtd7zb8.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.07.09.737611",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.07.09.737611v2.full",
  "id": "3t6rqegtd7zb8",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.07.09.737611v2",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioinformatics"
    ],
    [
      "openalex",
      "2740|Sarcoma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7168015494",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.07.09.737611v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3t6rqegtd7zb8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:26:38Z",
      "native_id": "10.64898/2026.07.09.737611",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.07.09.737611v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioinformatics",
      "subfield": "bioinformatics"
    }
  ],
  "title": "Spatial mitochondrial lineage tracing uncovers a premetastatic niche and microenvironment programmed fate switching in osteosarcoma",
  "title_text": "Spatial mitochondrial lineage tracing uncovers a premetastatic niche and microenvironment programmed fate switching in osteosarcoma",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:38Z",
  "url": "https://research.draconitic.com/paper/3t6rqegtd7zb8",
  "venue": "bioRxiv",
  "versions": []
}