Last week I blogged about a newly published article in the journal Molecular Cancer (link). In it, the authors compared the growth (in vitro and in vivo) of a cell line containing a series of wildtype or mutant FLCN transgenes; determining that wildtype FLCN suppressed xenograft tumour growth in vivo.
Gene expression profiling also showed that specific genes involved in angiogenesis, cadherin signalling and TGFβ signalling were differentially expressed in null or mutant FLCN expressing cell lines, compared to the wildtype. FLCN’s role in TGFβ signalling is the focus for the rest of the paper, rightfully so given the gravitas of TGFβ signalling in tumourigenesis. I also wonder whether the deregulation of angiogenesis and cadherin signalling are secondary adaptive measures that support tumourigenesis, or whether they occur downstream of the deregulation of TGFβ signalling in these tumours (or even both).
However, what I find particularly interesting is that when the authors examined how FLCN caused deregulation of TGFβ signalling, they showed that the phosphorylation status of downstream SMADs was unaffected by mutant FLCN, but that several downstream targets of TGFβ were, suggesting a role for FLCN in SMAD-independent TGFβ signalling. Whilst this finding is very exciting as it potentially places FLCN within a very specific signalling niche (potentially making it easier to examine), it may also prove to be a double edged sword since non-SMAD TGFβ signalling isn’t fully explored in itself, albeit because the SMADs themselves are so ubiquitous within the cell they’re a feature that can’t be ignored!