A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity

Abstract

Epithelial–mesenchymal transition (EMT) is an important axis of phenotypic plasticity—a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic ‘teams’ of players—while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.

Let-7restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis

“…Moreover, published studies on let-7 have shown that its loss stimulates cell growth and EMT programs, while its overexpression limits these processes 22,23 . Intriguingly, BACH1 and EZH2 have also been associated with partial EMT in cancer 53,54 , where epithelial cells linger as heterogeneous transitional cells which do not transition into mesenchymal cells but instead exhibit a continuum of epithelial and mesenchymal traits which potentiate migration, inflammation, and tumorigenesis 55 . Lineage tracing and scRNA-seq studies indicate that AT2 transitional cells do not transform into fibroblasts via EMT 10–13 ; instead, they adopt a mixed gene expression program characterized by simultaneous expression of epithelial and mesenchymal genes, which influences lung remodeling and ECM deposition 13,56 .…”