The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma

Patel, Anand G.; Chen, Xiang; Huang, Xin; Clay, Michael R.; Komorova, Natalia; Krasin, Matthew J.; Pappo, Alberto S.; Tillman, Heather; Orr, Brent A.; McEvoy, Justina; Gordon, Brittney; Blankenship, Kaley; Reilly, Colleen; Zhou, Xin; Norrie, Jacqueline L.; Karlström, Åsa; Yu, Jiyang; Wodarz, Dominik; Stewart, Elizabeth A.; Dyer, Michael A.

doi:10.1016/j.devcel.2022.04.003

Cited by 42 publications

(57 citation statements)

References 59 publications

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“…Here, we leveraged scRNAseq and CyTOF to analyze clinically relevant models of RMS and to dissect the cellular, molecular, and functional intratumoral heterogeneity. Our findings are in agreement with two recent publications ( 36 , 49 ), providing robust evidence in support of the hypothesis that both aRMS and eRMS tumors harbor developmentally halted cells with myogenic potential that fail to differentiate. Although the different studies provide no consensus on the nomenclature used to define RMS subpopulations [“mesoderm,” “myoblast,” and “myocyte” in ( 36 ); “mesenchymal-like,” “proliferation,” and “muscle” in ( 49 ); “MuSC-like,” “cycling progenitors,” and “differentiated” in our work], similar gene signatures suggest that the compartments are conceptually the same.…”

Section: Discussionsupporting

confidence: 93%

“…( H and I ) Comparison of intratumoral heterogeneity between preclinical models of aRMS. O-PDXs and patient tumor data are derived from ( 36 ). UMAP plots of individual models (H) and of the integrated datasets (I) are shown.…”

Section: Resultsmentioning

confidence: 99%

“…We wondered whether primary cultures and cell lines maintain the heterogeneity of the originating tumors, and therefore expanded our single-cell transcriptomic profiling to include orthotopic PDXs (O-PDXs) and patient tumors recently profiled by Patel et al. ( 36 ). We first focused on three eRMS samples, which were sequenced in both studies, and observed that primary cultures shared similar transcriptomic spaces of the originating O-PDXs and, when available, of the patient tumor (fig.…”

Section: Resultsmentioning

confidence: 99%

“…As there were no matched aRMS samples, we compared the heterogeneity of aRMS cell lines and primary cultures profiled in our study with O-PDXs and patient tumors profiled by Patel et al. ( 36 ). Patient tumors mainly mapped onto MuSC-like, G 1 -phase, and differentiated clusters and had fewer cells in the proliferating S-phase and cycling progenitor clusters, which were instead overrepresented in cell lines; primary cultures maintained a similar frequency of MuSC-like and differentiated cells than the patient tumors but higher abundance of S-phase and lower abundance of G 1 -phase cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We hypothesized that MuSC-like aRMS cells are either intrinsically resistant to treatment, as described for eRMS ( 36 ), or that chemotherapy rewires aRMS trajectories toward MuSC-like states. We assessed the in vitro efficacy of vincristine and 4-HC on sorted CD44 + and CD44 − cells (fig.…”

Section: Resultsmentioning

confidence: 99%

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Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

et al. 2023

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Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

et al. 2023

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Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future

Morel,

Rössler,

Bernasconi

2024

Medicinal Research Reviews

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Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Histology separates two main subtypes: embryonal RMS (eRMS; 60%–70%) and alveolar RMS (aRMS; 20%–30%). The aggressive aRMS carry one of two characteristic chromosomal translocations that result in the expression of a PAX3::FOXO1 or PAX7::FOXO1 fusion transcription factor; therefore, aRMS are now classified as fusion‐positive (FP) RMS. Embryonal RMS have a better prognosis and are clinically indistinguishable from fusion‐negative (FN) RMS. Next to histology and molecular characteristics, RMS risk groupings are now available defining low risk tumors with excellent outcomes and advanced stage disease with poor prognosis, with an overall survival of about only 20% despite intensified multimodal treatment. Therefore, development of novel effective targeted strategies to increase survival and to decrease long‐term side effects is urgently needed. Recently, immunotherapies and nanomedicine have been emerging for potent and effective tumor treatments with minimal side effects, raising hopes for effective and safe cures for RMS patients. This review aims to describe the most relevant preclinical and clinical studies in immunotherapy and targeted nanomedicine performed so far in RMS and to provide an insight in future developments.

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Patient-derived rhabdomyosarcoma cells recapitulate the genetic and transcriptomic landscapes of primary tumors

Hu,

He,

Liu

et al. 2024

iScience

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The myogenesis program drives clonal selection and drug resistance in rhabdomyosarcoma

Cited by 42 publications

References 59 publications

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance

Targeted immunotherapy and nanomedicine for rhabdomyosarcoma: The way of the future

Patient-derived rhabdomyosarcoma cells recapitulate the genetic and transcriptomic landscapes of primary tumors

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