The research in Varadarajan Lab involves understanding the role of apoptosis in diverse cellular processes, including intracellular stress response, organelle dynamics and homeostasis, in an attempt to achieve therapeutic effectiveness by modulating the functions of important signalling molecules in disease conditions. Our research vision can be further categorised into three broad areas:
BCL-2 family of proteins and cell death mechanisms
Most chemotherapeutic agents kill tumour cells by activating the intrinsic pathway of apoptosis, which requires the release of cytochrome c from mitochondria. Cancer cells often evade these events by overexpressing one or more anti-apoptotic BCL-2 family of proteins, such as BCL-2, BCL-XL and MCL-1, which function by sequestering and inhibiting their pro-apoptotic counterparts, such as BAX, BAK and BH3-only proteins, such as BIM, BID and NOXA. Disrupting these interactions using small molecule inhibitors (also known as BH3 mimetics) releases the bound pro-apoptotic BCL-2 family members to induce apoptosis. Whilst BH3 mimetics have demonstrated success in treating haematological malignancies, which often depend on either BCL-2, BCL-XL or MCL-1 for survival, solid tumours seem to depend on more than one of these members for survival. Given that all these proteins share a common mechanism of action in antagonising apoptosis, it is intriguing to observe such preferential dependency of different cancers for distinct anti-apoptotic BCL-2 family members. Moreover, these seemingly redundant proteins acquire new, major functions in these malignancies, when cells develop resistance during chemotherapy. Our lab is interested in studying these mechanisms, in an attempt to overcome chemoresistance in several cancers.
Endoplasmic Reticulum and mitochondrial membrane dynamics in apoptosis
Changes in mitochondrial membrane dynamics have frequently been associated with the loss of mitochondrial membrane potential, mitochondrial outer membrane permeabilisation (MOMP) and activation of the intrinsic pathway of apoptosis. We have reported that inhibitors of BCL-2 family members induced extensive mitochondrial fragmentation in a DRP-1 dependent manner. DRP-1 is a mitochondrial fission GTPase that not only facilitates mitochondrial fission but is also required for MOMP, thus coupling mitochondrial membrane dynamics and apoptosis. Most recent studies suggest a possible ‘wrapping’ of the Endoplasmic reticulum (ER) around the mitochondria to recruit DRP-1 and Dynamin-2 to facilitate mitochondrial fission and MOMP. Whether BCL-2 family members play critical roles in these events and if so, what are the underlying molecular mechanisms are questions for future research.
Metabolism and apoptosis
Caloric restriction has been reported to modulate MCL-1 expression and alter sensitivity to BH3 mimetic mediated apoptosis in lymphomas. Similarly, targeting metabolic pathways, such as glutaminolysis, has demonstrated promise as combination treatments with BH3 mimetics. This is an interesting avenue to pursue, as metabolic insults have also been implicated in decreasing tumour growth of several malignancies. In our lab, we are interested in understanding links between such metabolic insults and the mitochondrial apoptotic pathway, in order to explore the possibility of modulating cellular metabolism to enhance sensitivity to BH3 mimetics.
Identification and functional characterisation of novel drug combinations to improve therapy in head and neck cancer
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with an incidence three times the national average in some areas of Liverpool. Currently, most HNSCC patients are treated with a combination of surgery, radiation and/or chemotherapy. These treatment options, while improving survival rates particularly for early-stage disease, are associated with significant side effects, which often severely impact on survivors’ quality of life, highlighting the need for more specific and effective therapies. We have several projects that are aimed at exploring distinct cellular and metabolic pathways to improve therapy in HNSCC.