2. Academic Validation
  3. Spatially-Resolved Multiomic Atlas of Leiomyosarcoma Identifies Two Clinically Relevant Epigenetically-Driven Cell States

Spatially-Resolved Multiomic Atlas of Leiomyosarcoma Identifies Two Clinically Relevant Epigenetically-Driven Cell States

  • bioRxiv. 2026 May 26:2026.05.22.726988. doi: 10.64898/2026.05.22.726988.
Ryan A Denu 1,  Zhao Zheng 2,  Yingda Jiang 2,  Suresh Satpati 2,  Veena Kochat 2,  Kumaren Anand 3,  Danh D Truong 1,  Andrew R Lynch 4,  William Padron 2,  Davis R Ingram 5,  Khalida M Wani 5,  Diana Shamsutdinova 5,  Angela D Bhalla 6,  Sharon M Landers 6,  Ravin Ratan 1,  Neeta Somaiah 1,  Christina L Roland 6,  Keila E Torres 6,  Peter Van Loo 2 4,  Pamela T Soliman 7,  Larissa A Meyer 7,  Alexander J Lazar 2 5,  Emily Z Keung 7,  Elise F Nassif Haddad 1 8,  Kunal Rai 2
Affiliations

Affiliations

  • 1 Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 2 Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 3 Rice University, Houston, TX.
  • 4 Department of Genetics, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 5 Department of Pathology, Division of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 6 Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 7 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 8 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX.
PMID: 42244620 DOI: 10.64898/2026.05.22.726988
Abstract

Leiomyosarcoma is a smooth muscle-derived malignancy marked by significant clinical heterogeneity. The extent and nature of cellular heterogeneity and molecular underpinnings remain poorly understood. To address this at transcriptomic and epigenomic levels, we performed single-nucleus multiome Sequencing on untreated primary leiomyosarcoma tissues. Malignant cells segregated almost exclusively into two previously unrecognized and epigenetically distinct states: a dedifferentiated, mesenchymal-like subtype (MES) and a differentiated smooth muscle-enriched subtype (SMC). Chromatin accessibility profiling revealed strong enrichment of nuclear factor I (NFI) transcription factor motifs in MES cells, whereas AP-1 family motifs-most prominently FOSL2-were selectively accessible in SMC cells. Established leiomyosarcoma cell lines faithfully recapitulated these subtypes, and targeted depletion of NFI or AP-1 factors suppressed proliferation, invasion, and in vivo tumor growth, demonstrating functional dependency on these transcriptional programs. Spatial transcriptomics across 328 tissue cores from 128 leiomyosarcomas showed that immunosuppressive macrophages preferentially cluster around MES regions, revealing a subtype-specific tumor-immune niche. Clinically, MES-dominant tumors were associated with significantly worse patient outcomes. Through an epigenetic inhibitor screen, we identify and validate SMARCA4/2 inhibition as a promising therapeutic vulnerability for MES leiomyosarcomas. Together, this work defines two epigenetically driven, transcription factor-regulated, and clinically relevant states of leiomyosarcoma, revealing mechanistic underpinnings of tumor heterogeneity and uncovering actionable therapeutic strategies.

Keywords

NFI; cell states; epigenetics; epigenomics; leiomyosarcoma; multiome; plasticity; sarcoma; transcription factors; transcriptomics.

Figures
Products