Targeting ER homeostasis in multiple myeloma

The haematological malignancy multiple myeloma (MM) is typified by proliferation of clones producing excessive amounts of non-functional immunoglobulin, which interfere with normal haematopoietic functions in bone marrow. The plasma cells from which MM arises are highly optimised protein factories, assembling antibodies in the endoplasmic reticulum (ER) at rates nearing ~1x10³/cell/sec. Robust, adaptive quality control (QC) machinery safeguard integrity of this secretory cargo by facilitating maturation while eliminating aberrant (and potentially toxic) forms that invariably arise. These tandem activities enable the ER to maintain homeostasis while accommodating elevated rates of protein flux.

With a hypersecretory phenotype, MM is a disease tacitly relying on the QC machinery maintaining ER homeostasis to remain viable. Strategies that disrupt ER homeostasis have proved therapeutically beneficial for MM. Proteasome inhibitors (e.g. bortezomib) that block protein degradation which elevates ER stress to levels sufficient enough to activate cell death pathways and abate proliferation, exemplify this strategy. However, patients eventually become resistant to these compounds, likely due to cellular adaptation through enhancement of alternative protein degradation pathways. Thus, identifying cellular targets and processes in MM linked with ER homeostasis, which are non-redundant and thus more difficult to bypass and/or adapt to for viability (i.e. an Achilles heel), remains an important endeavour to find new therapeutic opportunities.

Our laboratory is defining the extensive network of ER-resident ubiquitination machinery, their functions and relationship to organelle homeostasis. Of particular interest are ubiquitin-related candidates that sensitise proteasome inhibitor-resistant model cell lines, as they may reflect alternative points for apoptotic entry. ER homeostasis mechanisms represent potentially valuable targets for therapeutic strategies to induce stress and cause cell death in MM. From our insight into the ubiquitination mechanisms at the ER, we are in search of those essential components whose disruption is able to induce ER stress and cell death and may represent new targets for therapeutic intervention.

My lab investigates how eukaryotic cells sense, respond to and resolve cellular stress through the mechanisms of protein quality control that ensure proteome fidelity. Cellular stress is a hallmark of cancers (e.g. multiple myeloma, prostrate, breast) and many other diseases and the integrated processes overseeing protein folding and degradation are essential for transformed cells to withstand the atypical and adverse conditions brought about by disease. We have a long-standing interest in the protein quality control mechanisms at work in the endoplasmic reticulum (ER) and, specifically, the molecular machinery and substrates of ER-associated degradation (ERAD); a multifaceted process responsible for clearing misfolded and surplus proteins from the ER through the ubiquitin-proteasome system.

We integrate proteomics, cell biology, functional genomics and biochemistry to identify essential ERAD factors, characterise functional complexes and understand how they enable cells to adapt to stress conditions associated with disease. Without these stringent protein quality control mechanisms in the ER, cells are unable to maintain homeostasis and do not survive when challenged by adverse conditions. Proliferating cancer cells frequently commandeer and become "addicted" to these stress response pathways to support their survival. This is why pharmacological agents that disrupt proteostasis (protein homeostasis) have been effective in the treatment of haematological malignancies such as multiple myeloma.

Our long-term goals involve identifying cellular proteins/complexes to target for the development of pharmacological strategies that interfere with cancer progression by disrupting the protein quality control mechanisms required for stress adaptation. Ubiquitination at the ER is an important regulator of both protein stability and function, and at the core of ERAD and ER stress resolution. More than 40 different proteins have already been implicated in ERAD alone; many as part of macromolecular complexes transiently forming around an estimated 25 ubiquitin ligases (E3s) resident to the ER membrane. As most E3s remain poorly characterised, we are focusing our efforts to identify important cofactors and targets of these E3 complexes in order to understand how they contribute to ER homeostasis and adaptation to stress. By finding ways to cripple one or more of these E3 complexes adaptively supporting ER stress resolution, we reason that this would render cancer cells less robust and consequently more susceptible to apoptosis.

Understanding the fundamental mechanisms and essential components that maintain, restore and adapt ER homeostasis in cancer are key research themes of our lab.