RT Journal Article
SR Electronic
T1 The Myogenesis Program Drives Clonal Selection and Drug Resistance in Rhabdomyosarcoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.16.448386
DO 10.1101/2021.06.16.448386
A1 Anand G. Patel
A1 Xiang Chen
A1 Xin Huang
A1 Michael R. Clay
A1 Natalia Komorova
A1 Matthew J. Krasin
A1 Alberto Pappo
A1 Heather Tillman
A1 Brent A. Orr
A1 Justina McEvoy
A1 Brittney Gordon
A1 Kaley Blankenship
A1 Colleen Reilly
A1 Xin Zhou
A1 Jackie L. Norrie
A1 Asa Karlstrom
A1 Jiyang Yu
A1 Dominik Wodarz
A1 Elizabeth Stewart
A1 Michael A. Dyer
YR 2021
UL http://biorxiv.org/content/early/2021/06/17/2021.06.16.448386.abstract
AB Rhabdomyosarcoma (RMS) is a pediatric cancer with features of skeletal muscle; patients with unresectable or metastatic RMS fare poorly due to high rates of disease recurrence. Here, we use single cell and single nucleus RNA-sequencing to show that RMS tumors recapitulate the spectrum of embryonal myogenesis. Using matched patient samples from a clinical trial and orthotopic patient-derived xenografts (O-PDXs), we show chemotherapy eliminates the most proliferative component with features of myoblasts; after treatment, the quiescent immature population with features of paraxial mesoderm expands to reconstitute the developmental hierarchy of the original tumor. We discovered that this paraxial mesoderm population is dependent on EGFR signaling and is sensitive to EGFR inhibitors. Taken together, this data serves as a proof-of-concept that targeting each developmental state in RMS is an effective strategy for improving outcomes by preventing disease recurrence.Competing Interest StatementThe authors have declared no competing interest.