Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy

Author:

Wu Lai Man Natalie1ORCID,Zhang Feng1ORCID,Rao Rohit1ORCID,Adam Mike2ORCID,Pollard Kai3,Szabo Sara1ORCID,Liu Xuezhao1ORCID,Belcher Katie A.1ORCID,Luo Zaili1,Ogurek Sean1ORCID,Reilly Colleen4ORCID,Zhou Xin4,Zhang Li5,Rubin Joshua6ORCID,Chang Long-sheng7ORCID,Xin Mei1ORCID,Yu Jiyang4ORCID,Suva Mario8ORCID,Pratilas Christine A.3ORCID,Potter Steven2,Lu Q. Richard1ORCID

Affiliation:

1. Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

2. Division of Developmental Biology, Brain Tumor Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA.

3. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

4. Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.

5. Environmental and Public Health Sciences, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.

6. Department of Neuroscience and Department of Neurology, Division of Hematology and Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.

7. Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA.

8. Department of Pathology and Department of Medicine, Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Abstract

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)–derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin+cells have been implicated as tumor stem cells in MPNST; unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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