Reference SummaryLangdon CG, Nat Commun 2021 Sep 17;12(1):5520

Title

 Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity.

Authors

 Langdon CG; Gadek KE; Garcia MR; Evans MK; Reed KB; Bush M; Hanna JA; Drummond CJ; Maguire MC; Leavey PJ; Finkelstein D; Jin H; Schreiner PA; Rehg JE; Hatley ME

Journal

 Nat Commun

Volume

 12

Issue

 1

Year

 2021

Pages

 5520

Abstract

 PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.

Links

 J:312395 – MGI References
34535684 – National Library of Medicine/PubMed

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Adipose tissue - Brown hibernoma Adipose tissue - Brown

0
[not specified]-Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr Adipose tissue - Brown hibernoma Adipose tissue - Brown

0
[not specified]-Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Adipose tissue - Brown tumor Adipose tissue - Brown

observed
[not specified]-Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr Adipose tissue - Brown tumor Adipose tissue - Brown

observed
[not specified]-Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Adipose tissue - White hyperplasia Adipose tissue - White

observed
[not specified]-Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr Adipose tissue - White hyperplasia Adipose tissue - White

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Head tumor Head

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Tg(Fabp4-cre)1Jmgr Head tumor Head

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Lymph node tumor Lymph node

0
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Tg(Fabp4-cre)1Jmgr Lymph node tumor Lymph node

0
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Smooth leiomyosarcoma Muscle - Smooth

observed
[not specified]-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Smooth leiomyosarcoma Muscle - Smooth

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma Muscle - Striated - Skeletal

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma Muscle - Striated - Skeletal

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma Muscle - Striated - Skeletal

0
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma Muscle - Striated - Skeletal

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan/+ Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma Muscle - Striated - Skeletal

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma - embryonal Muscle - Striated - Skeletal

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Muscle - Striated - Skeletal rhabdomyosarcoma - well differentiated Muscle - Striated - Skeletal

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr Neck tumor Neck

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Tg(Fabp4-cre)1Jmgr Neck tumor Neck

observed
[not specified]-Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

0
[not specified]-Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

0
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed - 91.67
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed - 81.82
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Trp53tm1Brn Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Trp53tm1Brn/+ Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Rb1tm2Brn Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Rb1tm2Brn/+ Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Cdkn2atm4Rdp Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Cdkn2atm4Rdp/+ Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze Gt(ROSA)26Sortm1(Smo/EYFP)Amc Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu/+ Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan/+ Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm14(CAG-tdTomato)Hze Gt(ROSA)26Sortm1(Smo/EYFP)Amc Pax7tm1.1Fan Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor (Unspecified organ)

observed
[not specified]-Gt(ROSA)26Sortm1(Smo/EYFP)Amc Ptentm1Hwu Tg(Fabp4-cre)1Jmgr (Unspecified organ) tumor - malignant (Unspecified organ)

observed