TY - JOUR
T1 - Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis
AU - Kim, Michael P.
AU - Li, Xinqun
AU - Deng, Jenying
AU - Zhang, Yun
AU - Dai, Bingbing
AU - Allton, Kendra L.
AU - Hughes, Tara G.
AU - Siangco, Christian
AU - Augustine, Jithesh J.
AU - Kang, Ya’An
AU - McDaniel, Joy M.
AU - Xiong, Shunbin
AU - Koay, Eugene J.
AU - McAllister, Florencia
AU - Bristow, Christopher A.
AU - Heffernan, Timothy P.
AU - Maitra, Anirban
AU - Liu, Bin
AU - Barton, Michelle C.
AU - Wasylishen, Amanda R.
AU - Fleming, Jason B.
AU - Lozano, Guillermina
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/8
Y1 - 2021/8
N2 - Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.
AB - Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.
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U2 - 10.1158/2159-8290.CD-20-1228
DO - 10.1158/2159-8290.CD-20-1228
M3 - Article
C2 - 33839689
AN - SCOPUS:85111154470
SN - 2159-8274
VL - 11
SP - 2094
EP - 2111
JO - Cancer Discovery
JF - Cancer Discovery
IS - 8
ER -