Exploring impacts of new technology

Chapters

• [0:00] Introduction & Speaker Background
• [0:53] Research Overview & Motivation
• [1:45] Live Imaging of Bone Marrow & Cell Behaviour
• [2:42] Understanding Bone Marrow Microenvironments
• [4:03] Plasma Cells, Bone Disease & Myeloma Biology
• [5:30] Mouse Models & Clonal Plasma Cell Clusters
• [7:54] Early Development of Myeloma & MGUS
• [10:08] Plasma Cell Growth & Slow Disease Progression
• [11:09] Genetic Changes in Myeloma & Lupus
• [13:31] Immune Responses, T Cells & Immunotherapy
• [18:44] Spatial Transcriptomics & New Technologies
• [25:32] Implications for Personalised Treatment
• [26:34] Key Takeaways & Future Directions

Transcript

[0:00]
Welcome everybody. It’s my pleasure to introduce our first presenter. Associate Professor Edwin Hawkins is an immunologist and cancer biologist. He completed his PhD at the Walter and Eliza Hall Institute before relocating to Peter Mac as a National Health and Medical Research Council Peter Doherty Fellow. In 2012, Edwin was awarded the European Hematology Young Investigator Fellowship to train in intravital microscopy at Imperial College London. He was recruited back to WEHI in October 2015 to establish a research program focused on haematopoiesis, inflammation and cancer, which he continues to lead today.

[0:53]
Thank you for that introduction, Laura, and apologies for all the long and annoying words. Today I’m going to share some research that has been a passion of mine for a long time. Even early in my career, this project was something I always hoped to pursue, which is one of the reasons I spent time training overseas. What you’re seeing here is an image of bone marrow with large clusters of myeloma-forming plasma cells. I’ll walk you through this story and how it relates to human disease, and I’d like to acknowledge that much of this work has been carried out by PhD students and collaborators within our lab and at Peter Mac.

[1:45]
In our laboratory, we specialise in imaging cells in live tissue, often using pre-clinical models. This allows us to observe tissue in action, in real time, as it would behave inside the body. The image shown here is bone marrow, with blood vessels and stem cells visible, and everything you’re seeing is happening live. This technology allows us to better understand biological processes that are very difficult to study using traditional cell culture methods.

[2:42]
A key concept I’ll be discussing today is the idea of microenvironments within the bone marrow. These are small, specialised niches that influence how cells behave and survive. In myeloma, plasma cells reside within these environments, and we believe they can hijack them to support disease progression and evade therapies, including immunotherapies. Understanding how these microenvironments form and function is critical to understanding why treatments sometimes fail and how myeloma cells survive for long periods of time.

[4:03]
Plasma cells are central to myeloma, but they are also involved in other conditions such as lupus. These cells originate from immune responses and migrate to the bone marrow, where they can persist for the lifetime of an individual. We know they interact with bone-forming cells and blood vessels, and that disruptions to these interactions contribute to bone disease and fractures commonly seen in myeloma.

[5:30]
Using mouse models, we can observe how myeloma develops within the bone marrow. Unlike other blood cancers, myeloma plasma cells form stable, localised clusters and remain relatively immobile. By labelling mutated plasma cells with fluorescent markers, we can track individual clones and observe how they establish and maintain their own microenvironments over time.

[7:54]
One of the striking findings from this work is that myeloma appears to begin much earlier than previously thought. In young mice that won’t develop symptoms for over a year, we already see plasma cell clusters forming in the bone marrow. This aligns with human data suggesting that early precursor conditions like MGUS are far more common than diagnosed, indicating that myeloma may develop slowly over many years.

[10:08]
By imaging the same regions of bone marrow over time, we’ve observed that plasma cell turnover is surprisingly slow. This challenges the idea that myeloma is driven by rapid cell proliferation and suggests instead that long-term survival within protective niches plays a major role in disease progression.

[11:09]
We’ve also applied genetic and spatial analysis techniques to understand what distinguishes these plasma cells at a molecular level. Interestingly, many of the genetic changes we observe in myeloma are shared with other plasma cell diseases, such as lupus, suggesting that these mechanisms are fundamental to plasma cell biology rather than unique to cancer.

[13:31]
A major focus of our work is understanding how myeloma interacts with the immune system, particularly T cells. Using live imaging, we can observe how immune cells infiltrate myeloma clusters and respond to therapies such as CAR T-cells and bispecific antibodies. While T cells can initially enter these areas and become activated, we’ve discovered that myeloma cells can induce T-cell death, which may explain why immune therapies can lose effectiveness over time.

[18:44]
To better understand these interactions, we use advanced spatial transcriptomics techniques that allow us to analyse gene expression directly within tissue. This enables us to see how different plasma cell clones create distinct microenvironments and how surrounding cells respond. Importantly, we are now applying these technologies to patient samples across different stages of myeloma.

[25:32]
What we’re learning is that no two plasma cell clones are the same. Each creates a unique microenvironment, some of which are permissive to immune activity and others that are highly suppressive. Understanding these differences may be key to improving immunotherapy and developing more personalised treatment approaches in the future.

[26:34]
I’ll finish by thanking the many collaborators and patients who have contributed to this work. Their generosity and dedication are critical to advancing our understanding of myeloma and ensuring that research remains relevant to patient care. Thank you, and I’m happy to take questions.