High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma

Generali, Melanie; Satheesha, Sampoorna; Bode, P.; Wanner, Debora; Schäfer, Beat W.; Casanova, Elisa A.

doi:10.3390/genes12091373

Cited by 4 publications

(3 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the authors did not detect a reversed switch from the differentiated state to mesenchymal-like state in eRMS ( 49 ), which could be a unique characteristic of the aggressive aRMS subtype. Our results are in line with a previous report that failed to detect a cancer stem cell (CSC) subpopulation with self-renewing and tumor-initiating properties in aRMS ( 51 ), rather suggesting a role for cellular plasticity instead of the classical CSC hypothesis at the root of this tumor resistance and aggressiveness.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 92%

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

et al. 2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous studies using fluorescent transgenic zebrafish bearing KRAS(G12D)induced RMS yielded similar insights [100]: GFP-labeled MYF5 high zebrafish tumor cells (expressing markers of satellite and early muscle progenitor cells) and mCherry-labeled MYF4 high zebrafish tumor cells (expressing high levels of mature muscle markers) were By contrast, PF+ RMS displays more prominent intrinsic plasticity, with both stem-like and cycling-myoblast states having the capacity to re-create the original composition of the tumor. These observations are consistent with in vivo tumor-propagating capacity of all single-cell clone-derived clones of P3F+ RMS cells examined by Generali et al [101]. Of note, fluctuating levels of P3F expression in single, mouse P3F+ RMS cells were linked to differences in in vitro clonal activity and in vivo tumor-propagating capacity, indicating plasticity in P3F expression at the single-cell level [91].…”

Section: Cellular Hierarchies In Rmssupporting

confidence: 89%

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Pomella

Danielli

Alaggio

et al. 2023

Cancers

Self Cite

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.

show abstract

“…Our work also suggests that FP-RMS may not follow the rigid-stem cell hierarchies found in development. In fact, limiting dilution cell transplantation assays using engraftment into immune deficient mice have shown that FP-RMS have a high frequency for tumor initiation [49], raising the possibility that most if not all FP-RMS cells can acquire the ability to propagate tumors in vivo . Such a model would be consistent with reports where drug-induced neuroendocrine transdifferentiation serves as an escape mechanism for melanoma and castration-resistant prostate cancer [50, 51].…”

Section: Discussionmentioning

confidence: 99%

Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma

Danielli,

Wei,

Dyer

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Rhabdomyosarcoma (RMS) is a pediatric tumor that resembles undifferentiated muscle cells; yet the extent to which cell state heterogeneity and molecular features are shared with human development have not been fully ascribed. Here, we report a single-cell/nucleus RNA sequencing atlas derived from 72 datasets that includes patient tumors, patient-derived xenografts, primary in vitro cultures, and established cell lines. We report four dominant muscle-lineage cell states in RMS: progenitors, proliferative, differentiated, and ground cells. We stratify these RMS cells along the continuum of human muscle development and show that RMS cells share expression patterns with fetal/embryonal myogenic precursors rather than postnatal satellite cells. Indeed, fusion-negative RMS (FN-RMS) have a discrete stem cell hierarchy that faithfully recapitulates fetal muscle development. We also identify therapy-resistant FN-RMS progenitor cells that share transcriptomic similarity with bipotent skeletal mesenchymal cells, while a subset of fusion-positive (FP) RMS have tumor-acquired cells states, including a neuronal cell state, that are not found in development. Chemotherapy induced upregulation of progenitor signatures in FN-RMS while the neuronal gene programs were retained after therapy in FP-RMS. Taken together, this work identifies new cell state heterogeneity including unique treatment-resistant and tumor-acquired cell states that differ across RMS subtypes.

show abstract

High Frequency of Tumor Propagating Cells in Fusion-Positive Rhabdomyosarcoma

Cited by 4 publications

References 64 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

Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Single cell transcriptomic profiling identifies tumor-acquired and therapy-resistant cell states in pediatric rhabdomyosarcoma

Contact Info

Product

Resources

About