Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas

Abstract

Additional prognostic and therapeutic biomarkers effective across different histological types of sarcoma are needed. Herein we evaluate expression of TAZ and YAP, the p53-MDM2 axis, and RABL6A, a novel oncoprotein with potential ties to both pathways, in sarcomas of different histological types. Immunohistochemical staining of a tissue microarray including 163 sarcomas and correlation with clinical data showed that elevated YAP and TAZ independently predict worse overall and progression-free survival, respectively. In the absence of p53 expression, combined TAZ and YAP expression adversely affect overall, progression free, and metastasis free survival more than TAZ or YAP activation alone. RABL6A independently predicted shorter time to metastasis and was positively correlated with p53, MDM2 and YAP expression, supporting a possible functional relationship between the biomarkers. Network analysis further showed that TAZ is positively correlated with MDM2 expression. The data implicate all five proteins as clinically relevant downstream players in the Hippo pathway. Finally, a novel inhibitor of MDM2 (MA242), effectively suppressed the survival of sarcoma cell lines from different histological types regardless of p53 status. These findings suggest both independent and cooperative roles for all five biomarkers across different histological types of sarcoma in predicting patient outcomes and potentially guiding future therapeutic approaches.

Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo

“…However, a recent histological analysis of multiple sarcoma subtypes, including MPNSTs, revealed positive correlations between YAP and RABL6A in the patient tumors whereas no direct associations between YAP and p53 were identified [17]. These studies suggest RABL6A may regulate YAP independent of p53 status.…”

“…Recent work identified YAP (Yes-Associated Protein), a potent oncogene and transcriptional regulator involved in Hippo signaling, as a driver of MPNST pathogenesis [25,26]. We identified a significant positive correlation between expression of YAP and RABL6A across numerous types of sarcoma, including MPNSTs [17]. We speculated that RABL6A loss may be associated with reduced YAP expression and activity in our MPNST tumor models.…”

“…3,3'diaminobenzidine (DAB, brown staining) was used as the chromogen, and Harris hematoxylin (basophilic staining) was used as the counterstain. Immunostaining for YAP and Ki67 was conducted utilizing validated protocols [17]. Antigen retrieval was performed using citrate buffer (pH 6.0), 110-125C for 6 5min, and 20min cool down.…”

“…RABL6A promotes the proliferation and survival of multiple tumor types, and its increased expression is a marker of poor survival in pancreatic adenocarcinoma [12], breast cancer [13,14], and non-small cell lung cancer [15,16]. Histochemical analyses of diverse patient sarcomas, including MPNSTs, showed RABL6A expression is associated with higher tumor grade and shorter time to metastasis [17]. In NF1 patient samples, RABL6A expression is upregulated during the stepwise transformation process with significantly higher levels in MPNSTs versus benign neurofibromas (NFs) [18].…”

Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo

“… 16 , 17 Histochemical analyses of diverse patient sarcomas, including MPNSTs, showed RABL6A expression is associated with higher tumor grade and shorter time to metastasis. 18 In NF1 patient samples, RABL6A expression is upregulated during the stepwise transformation process with significantly higher levels in MPNSTs versus benign neurofibromas (NFs). 19 Intermediate lesions, called atypical neurofibromatous neoplasms of uncertain biological potential (ANNUBP), displayed intermediate levels of RABL6A.…”