Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance.

Mannu K Walia,Ankita Gupte,T John Martin,Carl R Walkley,Scott Taylor,Alistair M Chalk,Alvin JM Ng,Patricia MW Ho,Andrew CW Zannettino

doi:10.7554/elife.13446

Mannu K Walia, Ankita Gupte + Show 7 more

Open Access

https://doi.org/10.7554/elife.13446

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Abstract

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.

Highlights

Mutations within the P53 pathway occur in all human cancers (Hanahan and Weinberg, 2011)
The altered transcript levels were reflected at the protein level, where loss of p53 was associated with an increase in total CREB1 and phosphorylated CREB1 in the KO cells (Figure 1B)
Using the fact that loss/mutation of TRP53 is essentially universal in OS, we modelled an initiating lesion in primary osteoblastic cells and used this to understand the consequences in these cells

Summary

Introduction

Mutations within the P53 pathway occur in all human cancers (Hanahan and Weinberg, 2011). The most prevalent mutations are point mutations that result in proteins with altered function (Olivier et al, 2010). In osteosarcoma (OS), the most common primary tumour of bone, unique genomic rearrangements and other mutation types most often result in null alleles of P53 (Ribi et al, 2015; Chen et al, 2014). The reason for this distinct TP53 mutational preference in osteoblastic cells, the lineage of origin of OS, is not understood, nor are the signaling cascades that are altered in p53-deficient osteoblastic cells that facilitate the initiation of OS. Understanding how the loss of P53 modifies osteoblast precursor cells to enable OS initiation will provide new avenues to improve clinical outcomes

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