Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma

Wei, Yun; Qin, Qian; Yan, Chuan; Hayes, Madeline; Garcia, Sara P.; Xi, Haibin; Do, Daniel; Jin, Alexander; Eng, Tiffany C.; McCarthy, Karin M.; Adhikari, Abhinav; Onozato, Maristela L.; Spentzos, Dimitrios; Neilsen, Gunnlaugur P.; Iafrate, A. John; Wexler, Leonard H.; Suvà, Mario L.; Cruz, Filemon S. Dela; Pinello, Luca; Langenau, David M.

doi:10.1038/s43018-022-00414-w

Cited by 21 publications

(37 citation statements)

References 60 publications

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“…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); "MuSClike," "cycling progenitors," and "differentiated" in our work], similar gene signatures suggest that the compartments are conceptually the same. A meta-analysis integrating the different RMS scRNAseq datasets will be needed to confirm this hypothesis.…”

Section: Discussionsupporting

confidence: 93%

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%

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

et al. 2023

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“…Thus, proliferating myoblasts at the end of the myogenic continuum described in this RMS-O model appear as 'halted' in an early stage of differentiation. This confirms recent studies on RMS tumor hierarchy, showing that cells with different degrees of differentiation mirror the normal developmental stages, but fail to completely differentiate and remain stalled in actively cycling progenitor states 37, 45 . We then asked if differences in apoptotic genes' expression and associated drug sensitivity may exist in those different reminiscent developmental myogenic states.…”

Section: The Definition Of Relevant Apoptotic-based Therapeutic Combi...supporting

confidence: 90%

“…Indeed, RMS-O models also preserve the intratumor heterogeneity of the original tumor. We were notably able to identify a developmental hierarchy within FNRMS comprising a quiescent satellite cell state, transitioning towards an activated mesenchymal-like state and halted-myoblasts, actively dividing and expressing early myogenic markers, thereby reproducing the incomplete muscle differentiation pattern described in RMS 37,45 . This reminiscent developmental program represents an interesting perspective to identify new therapeutic vulnerabilities that could be exploited to reduce disease recurrence.…”

Section: Discussionmentioning

confidence: 82%

“…Intra-tumoral heterogeneity is widely considered as a key driver of resistance to treatments 33,34 . To define whether our model preserves the recently described RMS tumor hierarchy reminiscent of human muscle development 37,45 , we generated droplet-based single-cell RNA sequencing (scRNA-seq) data on RMS-O using 10x Genomics’ technology. Overall, 14,371 tumoral cells (RMS1-0_P13 = 7608; RMS1-0_P14 = 6763) expressing a total of 33,538 transcripts and 15,175 detectable genes with more than 3 transcripts in at least one cell were quantified (Extended Data Fig.…”

Section: Resultsmentioning

confidence: 99%

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Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers

Savary

Huchedé

Luciana

et al. 2022

Preprint

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Rhabdomyosarcoma (RMS) is the main form of soft-tissue sarcoma in children and adolescents. For 20 years, and despite international clinical trials, its cure rate has not really improved, and remains stuck at 20% in case of relapse. The definition of new effective therapeutic combinations is hampered by the lack of reliable models, which complicate the transposition of promising results obtained in pre-clinical studies into efficient solutions for young patients. Inter-patient heterogeneity, particularly in the so-called fusion-negative group (FNRMS), adds an additional level of difficulty in optimizing the clinical management of children and adolescents with RMS. Here, we describe an original 3D-organoid model derived from relapsed FNRMS and show that it finely mimics the characteristics of the original tumor, including inter- and intra-tumoral heterogeneity. Moreover, we have established the proof-of-concept of its preclinical potential by re-evaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on the exploitation of bulk and single-cell omics data.

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“…Importantly, a majority of differential TADs between FP and FN-RMS were associated with genes involved in neurogenesis. Our findings provide a unique chromatin structural context for studies that find that FP-RMS tumors can express genes involved in neurogenesis (53,54).…”

Section: Resultsmentioning

confidence: 93%

The 3D chromatin landscape of rhabdomyosarcoma

Wang

Sreenivas²,

Sunkel

et al. 2022

Preprint

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Rhabdomyosarcoma (RMS) is a pediatric soft tissue cancer with a lack of precision therapy option for patients. We hypothesized that with a general paucity of known mutations in RMS, chromatin structural driving mechanisms are essential for tumor proliferation. Thus, we carried out high-depth in situ Hi-C in representative cell lines and patient-derived xenografts to understand chromatin architecture in each major RMS subtype. We report a comprehensive 3D chromatin structural analysis and characterization of fusion-positive (FP-RMS) and fusion-negative rhabdomyosarcoma (FN-RMS). We have generated spike-in in situ Hi-C chromatin interaction maps for the most common FP-RMS and FN-RMS cell lines, and compared our data with patient derived xenograft (PDX) models. In our studies we uncover common and distinct structural elements in large Mb-scale chromatin compartments, tumor-essential genes within variable topologically associating domains, and unique patterns of structural variation. Our comprehensive analysis provides high-depth chromatin interactivity maps for contextualizing gene regulation events identification of functionally critical chromatin domains in RMS.

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Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma

Cited by 21 publications

References 60 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

Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers

The 3D chromatin landscape of rhabdomyosarcoma

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