We have generated and characterized the first Pich KO mouse model (Albers et al, Cell Reports, 2018). PICH is a relevant protein involved in the resolution of ultra-fine anaphase bridges (UFBs) that derive from Common Fragile Sites (CFSs). We have found that PICH is essential for embryonic development due to the progressive accumulation of chromosomal instability. We have studied the influence of PICH on tumor initiation and progression. Particularly, we have used the lymphoma mouse model Emu-Myc in combination with Pich heterozygous and Pich conditional KO mice. Our results indicate that PICH deficiency delays the initiation and the progression of Myc-induced lymphoma (Castejón-Griñán et al., in preparation). Therefore, we believe that PICH is a promising therapeutic target for Myc-induced lymphomas and probably other cancer types.
On the other hand, we have successfully completed the first proteomics characterization of human CFSs. For that, we have implemented a FAND2-ChIP strategy coupled to Mass Spectrometry to identify dozens of proteins localizing at stressed CFSs. We have published this initial CFS-proteomics description, together with the characterization of one of the proteins identified -ATRX- at Nucleic Acid Research (Pladevall-Morera et al., Nuc Acid Res, 2019). We have found drugs that are toxic for ATRX deficient cancer cells (Pladevall-Morera D et al., Cancers, 2022), and we have characterized the relevance of SLX4IP maintaining CFS stability (Ingham et al, in preparation).
Finally, we have generated the first mouse model with a deletion of a whole CFS and we are finalizing our investigations related to the impact of FRA3B/FHIT loss in cancer and how FHIT deficiency can be exploited as a therapeutic opportunity.
