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Integrin- `10 Dependency Identifi Es RAC and RICTOR As Therapeutic Targets in High-Grade Myxofi Brosarcoma

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Integrin- `10 Dependency Identifi Es RAC and RICTOR As Therapeutic Targets in High-Grade Myxofi Brosarcoma Published OnlineFirst August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481 RESEARCH ARTICLE Integrin-`10 Dependency Identifi es RAC and RICTOR as Therapeutic Targets in High-Grade Myxofi brosarcoma Tomoyo Okada 1 , Ann Y. Lee 1 , Li-Xuan Qin 2 , Narasimhan Agaram 3 , Takahiro Mimae 1 , Yawei Shen 1 , Rachael O’Connor 1 , Miguel A. López-Lago 4 , Amanda Craig 1 , Martin L. Miller 5 , Phaedra Agius 1 , Evan Molinelli 5 , Nicholas D. Socci 5 , Aimee M. Crago 1 , 6 , Fumi Shima 7 , Chris Sander 5 , and Samuel Singer 1 , 6 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481 ABSTRACT Myxofi brosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profi ling of 64 pri- mary high-grade myxofi brosarcomas, we defi ned an expression signature associated with clinical out- come. The gene most signifi cantly associated with disease-specifi c death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofi brosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specifi c signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplifi cation on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had antitumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofi brosarcoma progression and provide the basis for promising targeted treat- ment strategies for patients with high-risk disease. SIGNIFICANCE: Identifying the molecular pathogenesis for myxofi brosarcoma progression has proven challenging given the highly complex genomic alterations in this tumor type. We found that integrin-α10 promotes tumor cell survival through activation of TRIO–RAC–RICTOR–mTOR signaling, and that inhibi- tors of RAC and mTOR have antitumor effects in vivo , thus identifying a potential treatment strategy for patients with high-risk myxofi brosarcoma. Cancer Discov; 6(10); 1148–65. ©2016 AACR. INTRODUCTION is currently regarded as a distinct fi broblastic/myofi broblastic tumor type defi ned by cellular pleomorphism, a curvilinear Myxofi brosarcoma is one of the most common histologic vascular pattern, and a myxoid stromal component ( 1–3 ). types of soft-tissue sarcoma in adults, typically occurring Although the mainstay of therapy is surgical resection, and in the extremities. Formerly known as a myxoid variant of 5-year disease-specifi c survival (DSS) after surgery for pri- malignant fi brous histiocytoma (a classifi cation representing mary high-grade myxofi brosarcoma is 60% to 70%, approxi- undifferentiated pleomorphic sarcomas), myxofi brosarcoma mately 30% to 40% of high-grade tumors metastasize to lung, bone, or lymph nodes ( 4–7 ). Once myxofi brosarcoma has metastasized, conventional chemotherapy and radiation 1 Sarcoma Biology Laboratory, Sarcoma Disease Management Program, therapy are largely palliative, and metastasis eventually leads Department of Surgery , Memorial Sloan Kettering Cancer Center, New York, New York. 2 Department of Biostatistics, Memorial Sloan Kettering Cancer to disease-related death. Center, New York, New York. 3 Department of Pathology, Memorial Sloan Ket- Prior genomic studies of myxofi brosarcoma have revealed tering Cancer Center, New York, New York. 4 Department of Surgery, Memorial no single characteristic genetic alteration; instead, single- Sloan Kettering Cancer Center, New York, New York. 5 Computational Biology nucleotide polymorphism (SNP) and array comparative 6 Center, Memorial Sloan Kettering Cancer Center, New York, New York. Depart- genomic hybridization (CGH) studies have shown that myxo- ment of Surgery, Weill Cornell Medical College, New York, New York. 7 Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan. fi brosarcoma is among the most highly complex sarcoma Note: Supplementary data for this article are available at Cancer Discovery types ( 8–10 ). The gene most commonly mutated was NF1 , Online (http://cancerdiscovery.aacrjournals.org/). mutated in 10.5% of myxofi brosarcomas. The most common T. Okada and A.Y. Lee contributed equally to this article. copy-number gain/amplifi cation was on 5p, occurring in 60% Current address for A.Y. Lee: New York University School of Medicine, New of myxofi brosarcomas ( 8 ). Among the genes in this amplicon, York, New York; current address for A. Craig: Department of Medicine, TRIO, SKP2, and AMACR were shown to be overexpressed, Icahn School of Medicine at Mount Sinai, New York, New York; current and SKP2 and AMACR were found to be potential oncogenes address for M.L. Miller: University of Cambridge, Cancer Research UK, in myxofi brosarcoma ( 11, 12 ). It remains unclear whether Cambridge Institute, UK; current address for P. Agius: New York Genome any other genes in the 5p amplicon serve as critical drivers Center, New York, New York; current address for E. Molinelli: BioDigital, Inc., New York, New York; and current address for C. Sander: cBio Center in myxofi brosarcoma. Because of the genetic and karyotypic at Dana-Farber Cancer Institute and Department of Cell Biology, Harvard complexity, defi ning the molecular pathogenesis underlying Medical School, Boston, Massachusetts. metastatic myxofi brosarcoma has been challenging and we Corresponding Authors: Samuel Singer , Memorial Sloan Kettering Cancer still lack targeted therapies against specifi c oncogenic path- Center, 1275 York Avenue, Howard 1205, New York, NY 10065. Phone: ways for this deadly sarcoma ( 10, 13 ). 212-639-2940; Fax: 646-422-2300; E-mail: [email protected]; and Integrins are cell-surface receptors that mediate the inter- Tomoyo Okada, Zuckerman Research Center, Memorial Sloan Kettering Cancer Center, 417 East 68th Street, ZRC445B, New York, NY 10065. action of cells with the microenvironment through binding Phone: 646-888-3205; E-mail: [email protected] to their ligands, extracellular matrix (ECM) proteins. Upon doi: 10.1158/2159-8290.CD-15-1481 ligand binding, activated integrins promote cellular adhesion © 2016 American Association for Cancer Research. and interact directly or indirectly with a number of proteins OCTOBER 2016CANCER DISCOVERY | 1149 Downloaded from cancerdiscovery.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481 RESEARCH ARTICLE Okada et al. to initiate cellular signaling for proliferation, migration, and size, the most important known clinical predictor in myxo- survival ( 14 ). Integrins are heterodimers composed of an alpha fi brosarcoma ( 4, 23–25 ). Both variables were independent and a beta subunit. Some aspects of ECM-integrin signaling predictors of DSS: tumor size as a continuous variable had a are known to be dysregulated in cancers, with pro-malignant hazard ratio of 1.15 (P = 0.010), and cluster 1 versus cluster 2 consequences such as promotion of stemness, survival in membership had a hazard ratio of 5.26 (P = 0.014). stressful environments, enhanced angiogenesis, resistance to There were 2,366 gene probes differentially expressed (at chemotherapy, and distant metastasis ( 15 ). Although integ- P < 0.001) between the two clusters (Supplementary Table rins alone do not transform cells, some of the pro-malignant S2). Of these 2,366 probes, 186 (representing 146 genes) were integrins associate with and signal through oncoproteins, also signifi cantly associated with DSS at P < 0.005 ( Fig. 1C such as SRC, FAK, and receptor tyrosine kinases ( 16, 17 ). and D ; see the full list in Supplementary Table S3). For 6 of Integrin-α10, isolated as a collagen II–binding integrin from the top-ranked genes, we remeasured expression by quantita- chondrocytes ( 18 ), is the alpha subunit of one of the colla- tive PCR and validated the associations with survival ( Fig. 1E ; gen II–receptor integrins (integrins α1β1, α2β1, and α10β1). Supplementary Fig. S1B). Integrin-α10 shows a restricted tissue expression pattern, most To provide biological context to the 146 survival-associated abundant in cartilage-containing tissues but also in fi brous genes, we used the NetBox algorithm ( 26 ) to analyze path- tissues such as the fascia lining skeletal muscle fi bers ( 19 ). ways. This algorithm identifi es modules of interconnected Integrin α10β1 is known from knockout studies to be essential genes from known human protein–protein and signal trans- for growth plate formation during skeletal development ( 20 ). duction pathway interactions. Using the 146 genes as input, Data are scarce on the role of integrin-α10 in human cancer. NetBox identifi ed 15 pathway modules, which exhibited a Integrin-α10 is overexpressed in primary and metastatic mela- stronger degree of connectedness (modularity) than expected noma cells and is associated with melanoma cell migration ( 21 ). by chance ( Fig. 1F ; Supplementary Table S4). Among the In contrast, in several other solid tumors, the downregulation modules with fi ve or more members, gene-annotation analysis of integrin-α10 is associated with loss of phosphorylated RB with the DAVID tool ( 27 ) revealed enrichment for
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