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.
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DOI：
10.1126/sciadv.ade9238
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发表时间：
2023-02-10
期刊：
影响因子：
13.6
通讯作者：
Schafer, Beat W.
中科院分区：
文献类型：
--
作者：
Danielli, Sara G.;Porpiglia, Ermelinda;De Micheli, Andrea J.;Navarro, Natalia;Zellinger, Michael J.;Bechtold, Ingrid;Kisele, Samanta;Volken, Larissa;Marques, Joana G.;Kasper, Stephanie;Bode, Peter K.;Henssen, Anton G.;Guergen, Dennis;Delattre, Olivier;Surdez, Didier;Roma, Josep;Buhlmann, Peter;Blau, Helen M.;Wachtel, Marco;Schafer, Beat W.
横纹肌肉瘤（RMS）是一组以发育中的骨骼肌为特征的儿科癌症。导致发育停滞的细胞层次和机制仍然难以捉摸。在这里，我们结合单细胞RNA测序，质谱仪，和高内容成像，以解决患者源性原发性RMS培养的瘤内异质性。我们发现，侵袭性肺泡RMS（aRMS）亚型包含可塑性肌肉干细胞样细胞和驱动肿瘤生长的循环祖细胞，以及失去增殖潜力并与更好结局相关的分化细胞亚群。虽然化疗消除了循环祖细胞，但它丰富了肌肉干细胞样细胞的aRMS。我们筛选了将aRMS劫持到临床上有利的亚群的药物，并鉴定了RAF和MEK抑制剂的组合，其有效地诱导肌源性分化并抑制肿瘤生长。总的来说，我们的工作提供了对aRMS侵袭性、耐药性和进展的潜在发育状态的见解，并将RAS通路确定为有希望的治疗靶点。RMS包含重演肌肉发育阶段的亚群，这些亚群可以被劫持向分化。
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. RMS contain subpopulations recapitulating muscle developmental stages, which can be hijacked towards differentiation.
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影响因子：
11.2
作者：
Boudjadi S;Pandey PR;Chatterjee B;Nguyen TH;Sun W;Barr FG
通讯作者：
Barr FG
影响因子：
11.2
作者：
Davicioni, Elai;Finckenstein, Friedrich Graf;Anderson, Michael J.
通讯作者：
Anderson, Michael J.
影响因子：
3.7
作者：
Finck, Rachel;Simonds, Erin F.;Jager, Astraea;Krishnaswamy, Smita;Sachs, Karen;Fantl, Wendy;Pe'er, Dana;Nolan, Garry P.;Bendall, Sean C.
通讯作者：
Bendall, Sean C.
影响因子：
50.3
作者：
Drummond CJ;Hanna JA;Garcia MR;Devine DJ;Heyrana AJ;Finkelstein D;Rehg JE;Hatley ME
通讯作者：
Hatley ME
DOI：
10.1126/science.aao4750
发表时间：
2018-04-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Filbin MG;Tirosh I;Hovestadt V;Shaw ML;Escalante LE;Mathewson ND;Neftel C;Frank N;Pelton K;Hebert CM;Haberler C;Yizhak K;Gojo J;Egervari K;Mount C;van Galen P;Bonal DM;Nguyen QD;Beck A;Sinai C;Czech T;Dorfer C;Goumnerova L;Lavarino C;Carcaboso AM;Mora J;Mylvaganam R;Luo CC;Peyrl A;Popović M;Azizi A;Batchelor TT;Frosch MP;Martinez-Lage M;Kieran MW;Bandopadhayay P;Beroukhim R;Fritsch G;Getz G;Rozenblatt-Rosen O;Wucherpfennig KW;Louis DN;Monje M;Slavc I;Ligon KL;Golub TR;Regev A;Bernstein BE;Suvà ML
通讯作者：
Suvà ML