Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits

Yuriko Sorimachi; Hiroshi Kobayashi; Yusuke Shiozawa; Shuhei Koide; Ryuichiro Nakato; Yukiko Shimizu; Tadashi Okamura; Katsuhiko Shirahige; Atsushi Iwama; Nobuhito Goda; Kaiyo Takubo; Keiyo Takubo

doi:10.1016/j.stemcr.2023.03.009

Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits

Stem Cell Reports. 2023 May 9;18(5):1211-1226. doi: 10.1016/j.stemcr.2023.03.009. Epub 2023 Apr 13.

Authors

Affiliations

¹ Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
² Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
³ Department of Pediatrics, The University of Tokyo, Tokyo 113-8655, Japan.
⁴ Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁵ Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; Laboratory of Computational Genomics, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
⁶ Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
⁷ Laboratory of Genome Structure and Function, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo 113-0032, Japan; Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Biosciences and Nutrition, Karolinska Institutet, 171 77 Stockholm, Sweden.
⁸ Department of Life Sciences and Medical BioScience, Waseda University School of Advanced Science and Engineering, Tokyo 162-8480, Japan.
⁹ Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
¹⁰ Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; Japan Agency for Medical Research and Development (AMED), Core Research for Evolutional Science and Technology (CREST), Tokyo 100-0004, Japan. Electronic address: keiyot@gmail.com.

Abstract

Soft tissue sarcomas (STSs) are a heterogeneous group of tumors that originate from mesenchymal cells. p53 is frequently mutated in human STS. In this study, we found that the loss of p53 in mesenchymal stem cells (MSCs) mainly causes adult undifferentiated soft tissue sarcoma (USTS). MSCs lacking p53 show changes in stem cell properties, including differentiation, cell cycle progression, and metabolism. The transcriptomic changes and genetic mutations in murine p53-deficient USTS mimic those seen in human STS. Furthermore, single-cell RNA sequencing revealed that MSCs undergo transcriptomic alterations with aging-a risk factor for certain types of USTS-and that p53 signaling decreases simultaneously. Moreover, we found that human STS can be transcriptomically classified into six clusters with different prognoses, different from the current histopathological classification. This study paves the way for understanding MSC-mediated tumorigenesis and provides an efficient mouse model for sarcoma studies.

Keywords: bone marrow; exome sequencing; mesenchymal stem cells; p53; single-cell RNA sequencing; soft tissue sarcoma; stem cell aging; stem cell metabolism.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Carcinogenesis / pathology
Cell Transformation, Neoplastic / metabolism
Humans
Mesenchymal Stem Cells* / metabolism
Mice
Sarcoma* / genetics
Sarcoma* / metabolism
Sarcoma* / pathology
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Tumor Suppressor Protein p53
TP53 protein, human