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 - Funding Information:
This work was supported by NIH/NCI K08CA218690 (to M.P. Kim), American College of Surgeons Faculty Research Fellowship (to M.P. Kim), NIH P01CA117969 (supported the generation and testing of PDX models), NIH/NCI R01CA82577 (to G. Lozano), and the NIH T32 CA 009599 (to T.G. Hughes). A. Maitra is supported by NIH/NCI R01CA220236. B. Liu is supported by CPRIT RP17002. We acknowledge Dr. Paulucci-Holthauzen at the BSRB Microscopy Facility for training and support and the NIH-shared instrumentation grant (1S10OD024976-01) for supporting the confocal microscope. The Cancer Center Support Grant (P30CA016672) supported all core facilities including the Flow Cytometry and Cellular Imaging Core Facility (FCCICF), the Functional Genomics Core, and the Advanced Technology Genomics Core. We acknowledge Jared Burks and Wendy Schober in the FCCICF for their assistance and support. We acknowledge the gracious support of the Richard K. Lavine Pancreatic Fund, the Ben and Rose Cole Charitable Pria Foundation, and the Skip Viragh Foundation for their generous support and dedication to pancreatic cancer research. Images were created with BioRender.com.
Funding Information:
E.J. Koay reports grants from NIH, Philips Healthcare, GE Healthcare, and Stand Up To Cancer, and personal fees from RenovoRx and Taylor and Francis LLC outside the submitted work. T.P. Heffernan reports other support from Boehringer Ingelheim and Taiho Pharmaceuticals, and personal fees from Cullgen Inc. and Silicon Therapeutics outside the submitted work. A. Maitra reports other support from Cosmos Wisdom Biotechnology and ThriveEarlier Detection outside the submitted work. G. Lozano reports grants from NCI during the conduct of the study. No disclosures were reported by the other authors.
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 -