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TWEAK-FN14 Pathway Promotes Prostate Cancer Bone and Brain Metastasis through EGR1-mediated Angiogenesis

Friday, September 15, 2017 — Poster Session IV

1:00 p.m. – 2:30 p.m.
FAES Terrace
NCI
CANCER-13

Authors

  • L Li
  • AH Ameri
  • J Yin
  • S Wang
  • KH Jansson
  • ML Beshiri
  • L Fang
  • R Lake
  • S Agarwal
  • AN Alilin
  • K Kelly

Abstract

Recurrence of prostate cancer (PCa) metastases after androgen deprivation therapy is a major clinical challenge. The molecular mechanisms driving metastasis in PCa remain poorly understood. We previously demonstrated that Fn14 (TNFRSF12A) is overexpressed significantly in metastatic lesions of PCa patients and is required for PCa metastasis through canonical NF¿B pathway in DU145/RasB1 cells. However, the downstream targets of TWEAK-FN14 pathway have yet to be characterized. We identified that EGR1 (Early Growth Response 1), a downstream effector of FN14, promotes PCa bone and brain metastasis. As a transcription factor, EGR1 is an early response gene involved in cell growth, differentiation, apoptosis, neurite outgrowth and wound healing. EGR1 was reported to stimulate tumorigenesis and correlate with Gleason grade in PCa; however, the pro-metastasis function of EGR1 in PCa is still elusive. In mice, TWEAK-FN14 activated EGR1 is required for bone and brain metastasis through angiogenesis. Analysis of patient samples indicated that EGR1 expression was upregulated in 40% of metastatic samples, but only 6% of primary tumors. EGR1 clustered with global gene expression of pro-angiogenic factors in primary and metastatic PCa. Additionally, EGR1 expression correlated with pro-angiogenic factors in both clinical samples, and a panel of metastatic patient derived xenografts (PDXs). In PDXs, FN14 and EGR1 were expressed, and EGR1 expression was upregulated at the protein level by TWEAK-FN14 activation. Our results define one downstream mechanism of FN14 signaling, through which EGR1-mediated angiogenesis contributes to PCa metastasis, and point to EGR1 as a candidate marker and therapeutic target for metastatic PCa.

Category: Cancer Biology