Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features
Menée sur des lignées cellulaires et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, lorsqu'elle est exprimée dans les fibroblastes associés au cancer du micro-environnement tumoral, la protéine p53 est susceptible de favoriser la progression de la tumeur
p53 research has primarily addressed its cell-autonomous tumor-suppressive features. Yet, recent evidence suggests that, in normal tissues, p53 can also exert cell nonautonomous tumor suppressor activities. Cancer-associated fibroblasts (CAFs) enhance the malignant features of adjacent cancer cells. Surprisingly, we found that the conversion of normal fibroblasts to CAFs entails nonmutational alteration of their p53, such that it now becomes cancer supportive rather than cancer inhibitory. This is achieved through reprogramming the transcriptional output of the CAF p53, rendering it a positive regulator of cancer-promoting genes and secreted proteins. Overall, our study highlights a function of nonmutated p53 in the tumor microenvironment and suggests that molecules that can “re-educate” the renegade p53 may have therapeutic value.Within the tumor microenvironment, cancer cells coexist with noncancerous adjacent cells that constitute the tumor microenvironment and impact tumor growth through diverse mechanisms. In particular, cancer-associated fibroblasts (CAFs) promote tumor progression in multiple ways. Earlier studies have revealed that in normal fibroblasts (NFs), p53 plays a cell nonautonomous tumor-suppressive role to restrict tumor growth. We now wished to investigate the role of p53 in CAFs. Remarkably, we found that the transcriptional program supported by p53 is altered substantially in CAFs relative to NFs. In agreement, the p53-dependent secretome is also altered in CAFs. This transcriptional rewiring renders p53 a significant contributor to the distinct intrinsic features of CAFs, as well as promotes tumor cell migration and invasion in culture. Concordantly, the ability of CAFs to promote tumor growth in mice is greatly compromised by depletion of their endogenous p53. Furthermore, cocultivation of NFs with cancer cells renders their p53-dependent transcriptome partially more similar to that of CAFs. Our findings raise the intriguing possibility that tumor progression may entail a nonmutational conversion (“education”) of stromal p53, from tumor suppressive to tumor supportive.