Glioblastoma multiforme is a highly complex, aggressive and deadly brain tumor. The rapidly expanding GBM tumor heterogeneity and recurrence, chemo and radio-resistance, oncogenic mutations, alternative splice variants, gene polymorphism and rapid chromatin remodelling has posed enormous difficulties in identifying the specific cellular targets.
The lead emerging concept at the frontiers of oncology is that the tumor cells maintain a very subtle balance of biomechanical forces such as the shear forces from the blood vessels, rigidity stresses from the stiffened extracellular matrix and glycocalyx clustering as well as the hydrostatic forces from the interstitial fluid accumulation.
The base idea therefore is to learn 'how' to misbalance the delicate force homeostasis to enable tumor cell death. Understanding of such principles will generate novel diagnostic and therapeutic regimes that will surpass the current complications encountered due to tumor heterogeneity.
Hence, our working hypothesis is that by better understanding the reciprocal mechanism between the cancer microenvironmental force generating agents and tumor mechanoadaptive circuitries, we may be in a position to hijack the hub molecular players which 'turn' tumor cells vulnerable to cell death. A 'target based' approach coupled with phenotypic screens that alter the physico-chemical characteristics of cancer cells, is therefore proposed in this research study for anti-GBM cancer drug discovery efforts.

Upcoming reports suggest that imbalances of biophysical forces on stem and progenitor cells in different organ systems may be one of the primary causative agent for the loss of proliferation control and transformation into tumor cells. However, an understanding of the principles underlying the processes of normal and pathogenic mechanosensing and mechanotransduction is at a very preliminary stage. We are concentrating on the plasma membrane resident modules called lipid rafts and its specialized form, the caveolae to trace the stem cell mechanocircuitries at different thresholds of rigidity and shear forces.

Galectins are recently being implicated to play crucial roles as both pro- and anti tumorigenic factors, however the precise mechanistic insights into their roles in generating tumor heterogeneity is missing. We find that several galectins are expressed simultaneously in any tumor and their combinatorial concentration levels may be crucial to the net outcome of the tumor fate. We are now trying to dissect the mechanism of action of galectins in tumorigenesis via an interdisciplinary approach involving surface mechanical remodelling principles.

Galectins is a family of beta-galactoside binding and non-classically secreted proteins that was initially identified in the process of axon pathfinding. Even though galectins' roles are now being established in several brain disorders such as in neuroblastoma and glioblastomas, dengue fever, ischemia, autism, multiple sclerosis and experimental allergic encephalomyelitis (EAE) etc., ironically, 'no systematic studies' have been performed on its expression, regulation and functions in brain's normal physiology. We have analyzed the in situ hybridization data from mouse and microarray data from human brain and have now validated the transcript expression with the protein expression. Results show that galectins' are expressed in both mouse and human brain but in a spatially heterogeneous pattern that may contribute to differential brain functions. In addition, we have identified galectins to be crucial targets of brain enriched transcription factors and further neuroinformatics analysis has predicted galectins to be functionally relevant in several brain processes such as neurogenesis, gliogenesis, cell proliferation, stem cell maintenance and differentiation, neurite extension, axonal growth, synaptogenesis and synaptic transmission. We are now dissecting the roles of each galectin in distinct brain functions and preliminary results suggests that galectins maybe intricately involved in presenting a regulative logic to brain architecture and functions.
The major highlights of the work so far that 1) Galectins have a highly heterogeneous transcript expression within and across mouse and human brain anatomical locations. 2) Galectins are predicted crucial targets of brain enriched transcription factors. 3) Galectin-1,-3,-8 and -9 may regulate several neuronal processes, while galectins-2,4,6,7 and 12 may regulate more specialized and localized functions. 4) Galectins-8 is most conserved across mouse and human brain. 5) Due to diverse regional distribution within and across species, may be considered as novel signatures of brain heterogeneity and functions.