Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

ITGA10

α

in vivo

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

NF1

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

β β β

β

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

in vitro in vivo

Gene expression profiles define two molecular subtypes of myxofibrosarcoma

p

p

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

p

p

p

Silencing of integrin- 10 induces growth suppression through apoptosis in

myxofibrosarcoma cells but not in normal mesenchymal cells

ITGA10

ITGA10

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

ITGA10

Forced expression of integrin- 10 enhances cell migration and invasion

Integrin- 10 regulates the activities of RAC/PAK and AKT in myxofibrosarcoma

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

TRIO and RICTOR are overexpressed via DNA amplification in myxofibrosarcoma and

physically associate with integrin- 10

TRIO RICTOR

TRIO

RICTOR

RICTOR

RICTOR TRIO

RICTOR TRIO

TRIO RICTOR

ITGA10

TRIO

TRIO RICTOR

TRIO RICTOR

TRIO RICTOR

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

TRIO and RAC are required for growth of myxofibrosarcoma cells

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

RICTOR is essential for activation of AKT and cell growth for myxofibrosarcoma cells,

but not ASCs

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Constitutively active RAC, PAK, and AKT rescue ITGA10 knockdown-induced growth

suppression and apoptosis

.

Pharmacologic inhibitors of RAC and mTORC inhibit growth of myxofibrosarcoma cells

in vitro

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

mTOR inhibition sensitizes myxofibrosarcoma cells to RAC inhibitors

EHop-016 and INK128 suppress myxofibrosarcoma primary and metastatic tumor growth

in mouse xenografts

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

ITGA10

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

β β

Itga10

TRIO

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

in vitro

in vitro

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

in vivo

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Patients

RNA isolation and microarray analysis

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Statistical Analysis

ITGA10 TRIO RICTOR

Pathway and Gene Annotation Analysis

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Copy Number Analysis

Cell Culture and Reagents

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Lentiviral transduction for shRNA and gene expression

Cell proliferation and apoptosis

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Migration and Matrigel invasion

Western Blotting

Biochemistry

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Collagen adhesion

Mouse tumorigenicity and metastasis

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

ITGA10

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

α

α

α

t P

P P

TRIO RICTOR

TRIO RICTOR

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

ITGA10

TRIO RICTOR TRIO

RICTOR

α

α

α

α

ITGA10 α

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

in vitro

α

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

α

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

p=0.0497

p=0.029p=0.043

p=0.019

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481

Published OnlineFirst August 30, 2016.Cancer Discov   Tomoyo Okada, Ann Y. Lee, Li-Xuan Qin, et al.   therapeutic targets in high-grade myxofibrosarcoma

10 dependency identifies RAC and RICTOR asαIntegrin-

  Updated version

  10.1158/2159-8290.CD-15-1481doi:

Access the most recent version of this article at:

  Material

Supplementary

 

http://cancerdiscovery.aacrjournals.org/content/suppl/2016/08/30/2159-8290.CD-15-1481.DC1.htmlAccess the most recent supplemental material at:

  Manuscript

Authoredited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been

   

   

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  .permissions@aacr.orgDepartment at

To request permission to re-use all or part of this article, contact the AACR Publications

Research. on September 12, 2016. © 2016 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 30, 2016; DOI: 10.1158/2159-8290.CD-15-1481