Mutated axon guidance gene PLXNB2 sustains growth and invasiveness of stem cells isolated from cancers of unknown primary

Abstract

The genetic changes sustaining the development of cancers of unknown primary (CUP) remain elusive. The whole-exome genomic profiling of 14 rigorously selected CUP samples did not reveal specific recurring mutation in known driver genes. However, by comparing the mutational landscape of CUPs with that of most other human tumor types, it emerged a consistent enrichment of changes in genes belonging to the axon guidance KEGG pathway. In particular, G842C mutation of PlexinB2 (PlxnB2) was predicted to be activating. Indeed, knocking down the mutated, but not the wild-type, PlxnB2 in CUP stem cells resulted in the impairment of self-renewal and proliferation in culture, as well as tumorigenic capacity in mice. Conversely, the genetic transfer of G842C-PlxnB2 was sufficient to promote CUP stem cell proliferation and tumorigenesis in mice. Notably, G842C-PlxnB2 expression in CUP cells was associated with basal EGFR phosphorylation, and EGFR blockade impaired the viability of CUP cells reliant on the mutated receptor. Moreover, the mutated PlxnB2 elicited CUP cell invasiveness, blocked by EGFR inhibitor treatment. In sum, we found that a novel activating mutation of the axon guidance gene PLXNB2 sustains proliferative autonomy and confers invasive properties to stem cells isolated from cancers of unknown primary, in EGFRdependent manner.

From Biology to Diagnosis and Treatment: The Ariadne’s Thread in Cancer of Unknown Primary

“…Moreover, plexins have been shown to couple with transmembrane tyrosine kinases such as ErbB2 and Met, triggering alternative noncanonical signalling cascades, especially in cancer cells [ 74 ]. A recent study demonstrated that G842C-mutated PlxnB2 was competent for signalling, even in the absence of semaphorin stimulation [ 75 ]. Moreover, although knocking down PlxnB2 expression in CUP cells bearing a wild-type receptor had no any functional impact, the metastatic cells carrying the G842C mutation were found to be dependent on this variant PlxnB2 to sustain self-renewal and proliferation in culture, along with tumorigenesis in mice.…”

Plexins as Regulators of Cancer Cell Proliferation, Migration, and Invasivity

“…In stem cells from cancers of unknown primary tumors, plexin-B2 that was mutated in its extracellular IPT domain (G842C) is constitutively active, promoting their ability to proliferate and their tumor-forming ability. Mutated plexin-B2 also promotes the invasiveness of these stem cells via association with and activation of EGFR ( Table 1 ) [ 69 ].…”