Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features

Sharathchandra Arandkar, Noa Furth, Yair Elisha, Nishanth Belugali Nataraj, Heiko van der Kuip, Yosef Yarden, Walter Aulitzky, Igor Ulitsky, Benjamin Geiger, Moshe Oren

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)6410-6415
Number of pages6
JournalProceedings Of The National Academy Of Sciences Of The United States Of America-Biological Sciences
Volume115
Issue number25
DOIs
StatePublished - 19 Jun 2018

All Science Journal Classification (ASJC) codes

  • General

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