The Myogenesis Program Drives Clonal Selection and Drug Resistance in Rhabdomyosarcoma

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2022 Apr 28

PMID 35483358

Authors

Anand G Patel

Xiang Chen

Xin Huang

Michael R Clay

Natalia Komorova

Matthew J Krasin

Alberto Pappo

Heather Tillman

Brent A Orr

Justina McEvoy

Brittney Gordon

Kaley Blankenship

Colleen Reilly

Xin Zhou

Jackie L Norrie

Asa Karlstrom

Jiyang Yu

Dominik Wodarz

Elizabeth Stewart

Michael A Dyer

Affiliations

Soon will be listed here.

Abstract

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 that chemotherapy eliminates the most proliferative component with features of myoblasts within embryonal RMS; after treatment, the 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, these data serve as a proof of concept that targeting each developmental state in embryonal RMS is an effective strategy for improving outcomes by preventing disease recurrence.

Citing Articles

Myogenesis gone awry: the role of developmental pathways in rhabdomyosarcoma.

Gustafson A, Durbin A, Artinger K, Ford H Front Cell Dev Biol. 2025; 12:1521523.

PMID: 39902277 PMC: 11788348. DOI: 10.3389/fcell.2024.1521523.

DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models.

Sun W, Hewitt S, Wright H, Keller C, Barr F J Pathol. 2025; 265(3):316-329.

PMID: 39812007 PMC: 11794984. DOI: 10.1002/path.6386.

Soft tissue sarcomas at the single-cell and spatial resolution: new markers and targets.

Menyailo M, Kopantseva E, Khozyainova A, Korobeynikova A, Denisov E Cancer Gene Ther. 2024; 32(1):11-21.

PMID: 39582085 DOI: 10.1038/s41417-024-00856-7.

ASAP1 and ARF1 Regulate Myogenic Differentiation in Rhabdomyosarcoma by Modulating TAZ Activity.

Hebron K, Perkins O, Kim A, Jian X, Girald-Berlingeri S, Lei H Mol Cancer Res. 2024; 23(2):95-106.

PMID: 39495123 PMC: 11799837. DOI: 10.1158/1541-7786.MCR-24-0490.

Single cell analysis revealed SFRP2 cancer associated fibroblasts drive tumorigenesis in head and neck squamous cell carcinoma.

Wang Q, Zhao Y, Tan G, Ai J NPJ Precis Oncol. 2024; 8(1):228.

PMID: 39384902 PMC: 11464629. DOI: 10.1038/s41698-024-00716-5.

References

Street K, Risso D, Fletcher R, Das D, Ngai J, Yosef N . Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics. 2018; 19(1):477. PMC: 6007078. DOI: 10.1186/s12864-018-4772-0. View

Cheng C, Easton J, Rosencrance C, Li Y, Ju B, Williams J . Latent cellular analysis robustly reveals subtle diversity in large-scale single-cell RNA-seq data. Nucleic Acids Res. 2019; 47(22):e143. PMC: 6902034. DOI: 10.1093/nar/gkz826. View

Langenau D, Keefe M, Storer N, Guyon J, Kutok J, Le X . Effects of RAS on the genesis of embryonal rhabdomyosarcoma. Genes Dev. 2007; 21(11):1382-95. PMC: 1877750. DOI: 10.1101/gad.1545007. View

Stewart E, Federico S, Chen X, Shelat A, Bradley C, Gordon B . Orthotopic patient-derived xenografts of paediatric solid tumours. Nature. 2017; 549(7670):96-100. PMC: 5659286. DOI: 10.1038/nature23647. View

Davis M, Hunt J, Herrgard S, Ciceri P, Wodicka L, Pallares G . Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011; 29(11):1046-51. DOI: 10.1038/nbt.1990. View

Shern J, Chen L, Chmielecki J, Wei J, Patidar R, Rosenberg M . Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov. 2014; 4(2):216-31. PMC: 4462130. DOI: 10.1158/2159-8290.CD-13-0639. View

Chen J, Ramachandran R, Goldhamer D . Essential and redundant functions of the MyoD distal regulatory region revealed by targeted mutagenesis. Dev Biol. 2002; 245(1):213-23. DOI: 10.1006/dbio.2002.0638. View

Wardle F . Master control: transcriptional regulation of mammalian Myod. J Muscle Res Cell Motil. 2019; 40(2):211-226. PMC: 6726840. DOI: 10.1007/s10974-019-09538-6. View

Blum J, Ano L, Li Z, Mater D, Bennett B, Sachdeva M . Distinct and overlapping sarcoma subtypes initiated from muscle stem and progenitor cells. Cell Rep. 2013; 5(4):933-40. PMC: 3893104. DOI: 10.1016/j.celrep.2013.10.020. View

10.

Buckingham M, Rigby P . Gene regulatory networks and transcriptional mechanisms that control myogenesis. Dev Cell. 2014; 28(3):225-38. DOI: 10.1016/j.devcel.2013.12.020. View

11.

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

12.

Ignatius M, Chen E, Elpek N, Fuller A, Tenente I, Clagg R . In vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in embryonal rhabdomyosarcoma. Cancer Cell. 2012; 21(5):680-693. PMC: 3381357. DOI: 10.1016/j.ccr.2012.03.043. View

13.

Stuart T, Srivastava A, Madad S, Lareau C, Satija R . Single-cell chromatin state analysis with Signac. Nat Methods. 2021; 18(11):1333-1341. PMC: 9255697. DOI: 10.1038/s41592-021-01282-5. View

14.

La Manno G, Soldatov R, Zeisel A, Braun E, Hochgerner H, Petukhov V . RNA velocity of single cells. Nature. 2018; 560(7719):494-498. PMC: 6130801. DOI: 10.1038/s41586-018-0414-6. View

15.

Wijaya J, Vo B, Liu J, Xu B, Wu G, Wang Y . An ABC Transporter Drives Medulloblastoma Pathogenesis by Regulating Sonic Hedgehog Signaling. Cancer Res. 2020; 80(7):1524-1537. PMC: 7416697. DOI: 10.1158/0008-5472.CAN-19-2054. View

16.

Wachtel M, Runge T, Leuschner I, Stegmaier S, Koscielniak E, Treuner J . Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry. J Clin Oncol. 2006; 24(5):816-22. DOI: 10.1200/JCO.2005.03.4934. View

17.

Bergen V, Lange M, Peidli S, Wolf F, Theis F . Generalizing RNA velocity to transient cell states through dynamical modeling. Nat Biotechnol. 2020; 38(12):1408-1414. DOI: 10.1038/s41587-020-0591-3. View

18.

Tan C, Gilligan D, Pacey S . Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015; 16(9):e447-e459. DOI: 10.1016/S1470-2045(15)00246-6. View

19.

Khatamian A, Paull E, Califano A, Yu J . SJARACNe: a scalable software tool for gene network reverse engineering from big data. Bioinformatics. 2018; 35(12):2165-2166. PMC: 6581437. DOI: 10.1093/bioinformatics/bty907. View

20.

Chen X, Stewart E, Shelat A, Qu C, Bahrami A, Hatley M . Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell. 2013; 24(6):710-24. PMC: 3904731. DOI: 10.1016/j.ccr.2013.11.002. View