Maria Korah, MD
General Surgery Resident
Stanford University
Stanford, California, United States
James P. Agolia, MD
General Surgery Resident
Stanford University
Stanford, California, United States
Biren Reddy, BA
Medical Student
Stanford University School of Medicine
Stanford, California, United States
Renceh Flojo, BS
Research Student
Stanford University
Stanford, California, United States
Amanda Gonçalves, BS
Life Science Research Professional
Stanford University
Stanford, California, United States
Lilin Wang, BS
Graduate Student
University of Minnesota
Minneapolis, Minnesota, United States
Rosyli F. Reveron-Thornton, MD, MS (she/her/hers)
General Surgery Resident
Stanford University
Stanford, California, United States
Chuner Guo, MD, PhD
Resident, Postdoctoral Scholar
Stanford University
Stanford, California, United States
Beatrice J. Sun, MD, MS (she/her/hers)
Resident
Stanford University School of Medicine
Stanford, California, United States
Amanda R. Kirane, MD PhD (she/her/hers)
Assistant Professor
Stanford University
Palo Alto, California, United States
George Poultsides, MD
Professor
Stanford University
Stanford, California, United States
Deshka Foster, MD PhD (she/her/hers)
Assistant Professor of Surgery
Stanford University
Stanford, California, United States
R. Stephanie Huang, PhD
Professor
University of Minnesota
Minneapolis, Minnesota, United States
Gregory Charville, MD, PhD
Associate Professor
Stanford University
Stanford, California, United States
Michael Longaker, MD
Deane P. and Louise Mitchell Professor in the School of Medicine
Stanford University
Stanford, California, United States
Byrne Lee, MD (he/him/his)
Clinical Professor, Surgery
Stanford University
Stanford, California, United States
Daniel Delitto, MD PhD
Assistant Professor of Surgery
Stanford University
Stanford, California, United States
Maria Korah, MD
General Surgery Resident
Stanford University
Stanford, California, United States
We performed single-cell RNA sequencing (scRNA-seq) on freshly collected ULMS tumors using the 10X Genomics platform and spatial transcriptomics on FFPE sections using the Singular G4X platform. Resulting cells were integrated with scVI or resolVI and annotated using canonical markers. Tumor signatures were correlated with patient outcomes using bulk RNA sequencing data and novel drugs predictions for each tumor cell subtype were computed using the scIDUC algorithm.
Results:
ScRNA-seq was performed on 15 recurrent, metastatic ULMS tumors from 13 patients at the time of debulking surgery, which yielded 204,250 high quality cells. Spatial transcriptomics was performed on 29 sections from 10 patients, which yielded 2.3 million spatially resolved cells. Both assays revealed heterogenous tumor microenvironments comprised of several types of cells, including myeloid cells, lymphoid cells, endothelial cells, and tumor cells. Among the tumor cells, eight subtypes with distinct signatures were identified, including 1) hormone receptor-positive stem-like cells scattered throughout the tumor, 2) metabolically adaptive Glycolytic cells with an inflammatory phenotype, 3) invasive Mesenchyme-like cells growing in fingerlike projections and surrounding blood vessels, and 4) MYC signaling cells that correlated with an ischemic tumor subtype surrounding areas of necrosis. Each tumor subset demonstrated unique associations with patient outcomes, with enrichment of MYC signaling cells correlating with the poorest survival. Current first-line therapies were predicted to be ineffective across most tumor subtypes; however, several alternative drug candidates uniquely targeting each tumor subtype were identified, including the broadly sensitive HDAC inhibitor tacedinaline.
Conclusions: We present a comprehensive transcriptomic and spatial atlas of ULMS, identifying several transcriptomic subtypes that correlate with patient outcomes and unique therapeutic sensitivities. Findings from this study will facilitate patient prognostication and the derivation of novel targeted therapeutic avenues.