Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 25, Pages 6410-6415Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1719076115
Keywords
p53; fibroblasts; matrix metalloproteinases; tumor microenvironment; lung cancer
Categories
Funding
- Robert Bosch Foundation [11.5.8000.0094]
- Sheldon G. Adelson Medical Research Foundation
- Center of Excellence Grant from the Israel Science Foundation [2084/15]
- Innovative Medicines Initiative Joint Undertaking [115188]
- Comisaroff Family Trust
- Moross Integrated Cancer Center
- Planning and Budgeting Committee of the Council for Higher Education (VATAT), Israel
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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.
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