Identification and Characterization of the Wilms Tumor Cancer Stem Cell

Astgik Petrosyan; Valentina Villani; Paola Aguiari; Matthew E Thornton; Yizhou Wang; Alex Rajewski; Shengmei Zhou; Paolo Cravedi; Brendan H Grubbs; Roger E De Filippo; Sargis Sedrakyan; Kevin V Lemley; Marie Csete; Stefano Da Sacco; Laura Perin

doi:10.1002/advs.202206787

Identification and Characterization of the Wilms Tumor Cancer Stem Cell

Adv Sci (Weinh). 2023 Jul;10(20):e2206787. doi: 10.1002/advs.202206787. Epub 2023 Apr 28.

Authors

Astgik Petrosyan^{1

2}, Valentina Villani¹, Paola Aguiari^{1

3}, Matthew E Thornton⁴, Yizhou Wang⁵, Alex Rajewski⁵, Shengmei Zhou⁶, Paolo Cravedi⁷, Brendan H Grubbs⁴, Roger E De Filippo^{1

2}, Sargis Sedrakyan^{1

2}, Kevin V Lemley^{2

8}, Marie Csete⁹, Stefano Da Sacco^{1

2}, Laura Perin^{1

2}

Affiliations

¹ GOFARR Laboratory, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, Los Angeles, CA, 90027, USA.
² Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
³ David Geffen School of Medicine at UCLA - VA Healthcare System, Los Angeles, CA, 90095, USA.
⁴ Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁵ Genomics Core, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
⁶ Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.
⁷ Department of Medicine, Division of Nephrology and Translational Transplant Research Center, Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
⁸ Children's Hospital Los Angeles, Division of Nephrology, Department of Pediatrics, University of Southern California, Los Angeles, CA, 90027, USA.
⁹ Department of Anesthesiology, University of Southern California, Los Angeles, CA, 90033, USA.

Abstract

A nephrogenic progenitor cell (NP) with cancer stem cell characteristics driving Wilms tumor (WT) using spatial transcriptomics, bulk and single cell RNA sequencing, and complementary in vitro and transplantation experiments is identified and characterized. NP from WT samples with NP from the developing human kidney is compared. Cells expressing SIX2 and CITED1 fulfill cancer stem cell criteria by reliably recapitulating WT in transplantation studies. It is shown that self-renewal versus differentiation in SIX2+CITED1+ cells is regulated by the interplay between integrins ITGβ1 and ITGβ4. The spatial transcriptomic analysis defines gene expression maps of SIX2+CITED1+ cells in WT samples and identifies the interactive gene networks involved in WT development. These studies define SIX2+CITED1+ cells as the nephrogenic-like cancer stem cells of WT and points to the renal developmental transcriptome changes as a possible driver in regulating WT formation and progression.

Keywords: Wilms tumor; cancer; nephron progenitors.

Publication types

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

MeSH terms

Humans
Kidney
Kidney Neoplasms* / genetics
Neoplastic Stem Cells / metabolism
Transcription Factors / genetics
Wilms Tumor* / genetics
Wilms Tumor* / metabolism
Wilms Tumor* / pathology

Substances

Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding