TY - JOUR
T1 - Altered p53 functionality in cancer-associated fibroblasts contributes to their cancer-supporting features
AU - Arandkar, Sharathchandra
AU - Furth, Noa
AU - Elisha, Yair
AU - Belugali Nataraj, Nishanth
AU - van der Kuip, Heiko
AU - Yarden, Yosef
AU - Aulitzky, Walter
AU - Ulitsky, Igor
AU - Geiger, Benjamin
AU - Oren, Moshe
N1 - Publisher Copyright: © 2018 National Academy of Sciences. All Rights Reserved.
PY - 2018/6/19
Y1 - 2018/6/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048930953&partnerID=8YFLogxK
U2 - https://doi.org/10.1073/pnas.1719076115
DO - https://doi.org/10.1073/pnas.1719076115
M3 - مقالة
SN - 0027-8424
VL - 115
SP - 6410
EP - 6415
JO - Proceedings Of The National Academy Of Sciences Of The United States Of America-Biological Sciences
JF - Proceedings Of The National Academy Of Sciences Of The United States Of America-Biological Sciences
IS - 25
ER -