The NFIB‐ERO1A axis promotes breast cancer metastatic colonization of disseminated tumour cells

• Published in: EMBO molecular medicine 2021-04, Vol.13 (4), p.e13162-n/a
• Main Authors: Zilli, Federica, Marques Ramos, Pedro, Auf der Maur, Priska, Jehanno, Charly, Sethi, Atul, Coissieux, Marie‐May, Eichlisberger, Tobias, Sauteur, Loïc, Rouchon, Adelin, Bonapace, Laura, Pinto Couto, Joana, Rad, Roland, Jensen, Michael Rugaard, Banfi, Andrea, Stadler, Michael B, Bentires‐Alj, Mohamed
• Format: Article
• Language: English
• Subjects: Angiogenesis; Breast cancer; Breast Neoplasms - genetics; Colonization; EMBO03; EMBO37; EMBO46; ERO1A; Female; Genes; Genomes; Humans; Kinases; Metastases; Metastasis; Mutagenesis; Mutation; Neovascularization, Pathologic; NFI Transcription Factors; NFIB; Oxidoreductase; Oxidoreductases; Tetracycline; Tetracyclines; Transposon mutagenesis; Transposons; Tumors; VEGFA
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202013162

Metastasis is the main cause of deaths related to solid cancers. Active transcriptional programmes are known to regulate the metastatic cascade but the molecular determinants of metastatic colonization remain elusive. Using an inducible piggyBac (PB) transposon mutagenesis screen, we have shown that overexpression of the transcription factor nuclear factor IB (NFIB) alone is sufficient to enhance primary mammary tumour growth and lung metastatic colonization. Mechanistically and functionally, NFIB directly increases expression of the oxidoreductase ERO1A , which enhances HIF1α‐VEGFA‐mediated angiogenesis and colonization, the last and fatal step of the metastatic cascade. NFIB is thus clinically relevant: it is preferentially expressed in the poor‐prognostic group of basal‐like breast cancers, and high expression of the NFIB/ERO1A/VEGFA pathway correlates with reduced breast cancer patient survival. Synopsis Transcriptional factor nuclear factor IB (NFIB) is sufficient to enhance lung metastatic colonization via enhanced angiogenesis, thus revealing a targetable network that promotes breast cancer colonization. NFIB was identified via an unbiased ex vivo piggyBac (PB) transposon insertional mutagenesis screen, and validated as an inducer of metastatic colonization in breast cancer. NFIB directly enhances ERO1A oxidoreductase expression, which in turn increases intracellular ROS levels, stabilizes HIF1alpha protein in the nucleus and upregulates VEGFA expression. Functionally, the NFIB‐ERO1A‐VEGFA axis enhances angiogenesis, promotes metastatic colonization and shortens overall survival of the animals. A correlation was found between NFIB, ERO1A, and VEGFA co‐expression and the metastatic potential in PDX models. Graphical Abstract Transcriptional factor nuclear factor IB (NFIB) is sufficient to enhance lung metastatic colonization via enhanced angiogenesis, thus revealing a targetable network that promotes breast cancer colonization.