In Vivo Imaging of Tumor-Propagating Cells, Regional Tumor Heterogeneity, and Dynamic Cell Movements in Embryonal Rhabdomyosarcoma

Ignatius, Myron S.; Chen, Eleanor; Elpek, Natalie; Fuller, Adam Z.; Tenente, Inês M.; Clagg, Ryan; Liu, Sali; Blackburn, Jessica S.; Linardic, Corinne M.; Rosenberg, Andrew E.; Nielsen, Petur; Mempel, Thorsten R.; Langenau, David M.

doi:10.1016/j.ccr.2012.03.043

Cited by 105 publications

(152 citation statements)

References 32 publications

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“…The animal studies were approved by the Massachusetts General Hospital Subcommittee on Research Animal Care under protocol #2012N000127 (zebrafish). Fluorescence-labeled ERMS were created by microinjecting the rag2: kRASG12D transgene into mylz2-mCherry transgenic, one-cell stage syngeneic zebrafish (13) and transplanted into 5-to 6-wk-old nonfluorescent, CG1-strain recipient fish (2.5 × 10 4 unsorted cells per fish, 2-μL volume). ERMSengrafted fish were imaged and then exposed to drug or DMSO vehicle in six-well plates (two fish per well, n = 4-8 animals per drug treatment).…”

Section: Discussionmentioning

confidence: 99%

“…To distinguish between the two possibilities, we took advantage of our myf5: GFP/mylz2:mCherry transgenic zebrafish line to label distinct subpopulations of ERMS cells according to their differentiation status in vivo. Our previous studies have shown that the myf5: GFP + /mylz2:mCherry − TPC population exclusively retains selfrenewal capacity, whereas late-differentiating myf5:GFP − /mylz2: mCherry + tumor cells lack both the capacity to self-renew and to metastasize (13,14). After 5-d drug treatment of animals engrafted with myf5:GFP/mylz2:mCherry expressing ERMS, relative proportions of ERMS cell subpopulations were assessed by FACS (n = 3 independent primary tumors).…”

Section: Gsk3 Inhibitors Activate the Wnt/β-catenin Pathway To Stimulatementioning

confidence: 99%

“…The prognosis for relapsedriven by retention of self-renewing TPCs after treatment-remains dismal, with 50% of patients succumbing to their disease. Using a zebrafish transgenic model of ERMS where an activated form of Kirsten rat sarcoma viral oncogene (K-RAS) is expressed in early muscle cells, we have identified a molecularly defined population of cells that drive continued tumor growth (13,14). These TPCs express muscle stem cell markers, including cMet, m-cadherin, and myogenic factor 5 (myf5), and exhibit a conserved gene expression profile found in human and mouse activated satellite cells.…”

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Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Chen

DeRan

Ignatius

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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126

127

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Embryonal rhabdomyosarcoma (ERMS) is a common pediatric malignancy of muscle, with relapse being the major clinical challenge. Selfrenewing tumor-propagating cells (TPCs) drive cancer relapse and are confined to a molecularly definable subset of ERMS cells. To identify drugs that suppress ERMS self-renewal and induce differentiation of TPCs, a large-scale chemical screen was completed. Glycogen synthase kinase 3 (GSK3) inhibitors were identified as potent suppressors of ERMS growth through inhibiting proliferation and inducing terminal differentiation of TPCs into myosin-expressing cells. In support of GSK3 inhibitors functioning through activation of the canonical WNT/ β-catenin pathway, recombinant WNT3A and stabilized β-catenin also enhanced terminal differentiation of human ERMS cells. Treatment of ERMS-bearing zebrafish with GSK3 inhibitors activated the WNT/ β-catenin pathway, resulting in suppressed ERMS growth, depleted TPCs, and diminished self-renewal capacity in vivo. Activation of the canonical WNT/β-catenin pathway also significantly reduced selfrenewal of human ERMS, indicating a conserved function for this pathway in modulating ERMS self-renewal. In total, we have identified an unconventional tumor suppressive role for the canonical WNT/ β-catenin pathway in regulating self-renewal of ERMS and revealed therapeutic strategies to target differentiation of TPCs in ERMS.

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Section: Discussionmentioning

confidence: 99%

Section: Gsk3 Inhibitors Activate the Wnt/β-catenin Pathway To Stimulatementioning

confidence: 99%

mentioning

confidence: 99%

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Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Chen

DeRan

Ignatius

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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126

127

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“…Once they have established a new tumor site, the less differentiated myf5-positive cells migrate into the newly forming tumor, ultimately driving tumor expansion and progression. 125,126 This implicates that the less differentiated RMSpropagating cells may take advantage of specific nutrients produced by the neighboring more differentiated cells during tumor dissemination, a process that might be even influenced by the proportion of fast or slow twitch muscle fibers potentially releasing specific metabolites around the tumor niche (at least when the tumor arises in muscle beds). This scenario seemingly resembles the so-called reverse Warburg effect, in which epithelial cancer cells were found to corrupt the stroma associated fibroblasts undergoing myo-fibroblastic differentiation to release micronutrients in the milieu, such as lactate and pyruvate, which are then taken up by cancer cells to produce energy in the mitochondria.…”

Section: Targeting Intratumor Cell Heterogeneity: a Difficult But Promentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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“…Phenotypically and functionally distinct subsets of cells with differential ability to repopulate tumors in secondary recipients, to selfrenew, and to migrate were identified in models of fusion-negative RMS (Walter et al 2011;Ignatius et al 2012). However, potential differences in drug sensitivities between individual RMS cell subsets and their clonal evolution over time are not known.…”

Section: Critical Biological Problemsmentioning

confidence: 99%

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

Hettmer¹,

Li²,

Billin³

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNAbinding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 ( previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in ,30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusionpositive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.

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In Vivo Imaging of Tumor-Propagating Cells, Regional Tumor Heterogeneity, and Dynamic Cell Movements in Embryonal Rhabdomyosarcoma

Cited by 105 publications

References 32 publications

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Glycogen synthase kinase 3 inhibitors induce the canonical WNT/β-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma

Uncovering metabolism in rhabdomyosarcoma

Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

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