Role of Cell-Cell Interaction and Signaling in GBM
Using our in vitro radiation resistance model of GBM, we have reported that the residual cells that are transiently non-proliferative and senescent, are enriched in multinucleated and giant cells (MNGCs), formed as a result of homotypic cell-cell fusions. However, these MNGCs are capable of overcoming mitotic catastrophe and undergo division to form mononucleated relapse population (Kaur et al., Carcinogenesis 2015).
Since these residual cells are solely responsible for the formation of relapse tumor cells, we are focused on understanding the biology of transition from parent to residual and relapse cells. For this, we performed a whole proteomic and transcriptome analysis of the parent, residual and relapse population generated from the cellular model. From our proteomic analysis, we have recently reported that the proteasome pathway is upregulated in the residual population, and inhibition of this pathway results in radio-sensitization of GBM cells and abrogates relapse (Rajendra et al., Oncotarget 2017). From our transcriptome analysis, we are trying to understand the mechanistic regulation of ATF3 – a stress-response protein and DUSP6 phosphatase – a negative regulator of ERK pathway in mediating tumor recurrence in GBM.
Furthermore, in order to identify the molecular players involved in homotypic cell fusion events active during the transient non-proliferative phase, we have performed a surface-proteome analysis, in which we are currently scrutinizing the unique plasma membrane proteins differentially expressed in residual cells and potentially involved in cell-cell fusions. Specific targeting of these proteins may help in selective elimination of residual resistant cells, thereby preventing GBM relapse. Secondly, for elucidating the molecular mechanisms by which these MNGCs divide and give rise to mononucleated relapse population, we are investigating the candidate molecular players involved in cell division, whose selective inhibition may help in preventing tumor recurrence.