PLASTECITY: it takes a village to grow a leukaemia

Breaking barriers in leukaemia treatment by targeting plasticity of the bone marrow microenvironment.

Acute myeloid leukaemia (AML) is an aggressive blood cancer that affects thousands of people worldwide. It’s particularly challenging to treat because current therapies often don’t fully eliminate the cancer, leading to relapses. AML mainly affects the bone marrow, the soft tissue inside bones where blood cells are made. Today, the primary treatment for AML is high-dose chemotherapy, which can have severe side effects and doesn’t always stop the cancer from returning.

While AML is generally seen as a disease caused by genetic changes in blood cells, recent research shows that there’s more to the story. AML cells cannot sustain themselves independently, as they require a number of signals from their surrounding environment. Recent research shows that AML causes changes in the bone marrow’s environment during this toxic interaction, particularly in the blood vessels that support blood production. The PLASTECITY project—short for ‘Plasticity of Endothelial Cells’—aims to understand and ultimately target this process. By exploring how AML affects the plasticity, or flexibility, of these blood vessel cells in the bone marrow, PLASTECITY could lead to new therapies and reduce the rate of relapse for AML patients.

What’s new in the AML microenvironment?

Our research through PLASTECITY focuses on a surprising new aspect of AML: how it affects the blood vessels in the bone marrow, a part of the tissue traditionally overlooked in cancer treatment. Blood vessels are lined with endothelial cells (ECs), a type of cell that forms a barrier between the blood and surrounding tissues. These cells are stable in healthy bones and help support blood production and bone turnover. However, in AML patients, these endothelial cells undergo significant changes, adopting characteristics more commonly seen in embryos.

This change in the endothelial cells—which we refer to as a ‘plastic-like’ state—suggests that these cells in AML are becoming more flexible. Plasticity means that these cells can change their identity and possibly even take on different roles, a property usually seen in stem cells or very early developmental cells. This unusual transformation could be helping AML cells survive in the bone marrow, making the disease harder to treat.

Deciphering the ‘plastic’ nature of endothelial cells in AML

To understand this process, PLASTECITY closely examines how these endothelial cells change in AML. Our research found that as AML progresses, more and more endothelial cells show signs of reverting to a more flexible, plastic-like state. Normally, these cells are tightly connected, forming a stable barrier. But in AML, their connections break down, perturbing cellular trafficking and drug delivery.

PLASTECITY will use advanced techniques like in vivo lineage tracing, a method to track specific cell types in live animals over time, and OMIC studies, which aim to uncover the deep molecular nature of these cells. By studying both animal models and patient samples, we can map out how these endothelial cells are transforming and see if they might even start to look like other types of cells, such as haematopoietic (blood-forming) or mesenchymal cells and cancer-associated fibroblasts. This transformation might play a major role in helping leukaemia cells survive and grow in the bone marrow.

Why targeting these cells could be a game-changer in AML treatment

The ultimate goal of the PLASTECITY project is to find new ways to treat AML by targeting this process of endothelial cell transformation. By stopping these cells from reverting to their plastic-like state, we could make the bone marrow a less hospitable environment for leukaemia cells. This approach has the potential to make AML treatments more effective, potentially reducing relapses and improving long-term survival.

PLASTECITY aims to identify specific ‘candidate genes’ in these transformed endothelial cells that new therapies could target. To do this, we’re using cutting-edge tools like CRISPR-nanobodies, a type of gene-editing technology, to selectively ‘switch off’ certain genes in these cells. By targeting these genes, we can directly test whether stopping these changes in endothelial cells affects leukaemia growth. In other words, we’re looking for ways to make the bone marrow environment less favourable to leukaemia, reducing the chances of the disease coming back after treatment.

Translating findings to real-world applications with the bone marrow-on-chip

After identifying these potential targets, we need to test our findings in models that closely resemble the human body. This is where PLASTECITY’s innovative ‘bone marrow-on-chip’ technology comes in. This tool is essentially a small-scale, engineered version of human bone marrow that mimics the conditions in the human body more accurately than traditional laboratory methods. By testing our treatments on the bone marrow-on-chip, we can see how they might work in real patients.

This platform allows us to validate our findings with patient-derived cells and analyse how targeting these transformed endothelial cells could impact leukaemia growth. The bone marrow-on-chip can be customised to simulate the specific environment found in AML patients, giving us a way to closely observe how our targeted therapies might work in a clinical setting.

Implications and the road ahead

The knowledge we will gain from PLASTECITY could open up entirely new avenues for treating AML. By focusing on the bone marrow environment itself and targeting the changes AML causes in endothelial cells, we’re approaching the disease from a fresh angle. If we can prevent these cells from supporting leukaemia, we could develop therapies that work alongside existing treatments to create a more comprehensive approach. This could mean better outcomes for patients, fewer side effects and, ultimately, a lower risk of relapse.

In the long run, this research could also help us understand other types of cancer and blood disorders where the bone marrow environment plays a role. Many cancers have been shown to alter their surrounding environments to create conditions that allow them to survive. By understanding the fundamental ways in which cancer cells can reshape their environment, we could improve treatments for a range of diseases.

Moving towards a future with better AML treatments

In conclusion, PLASTECITY aims to tackle AML from a different angle by exploring how leukaemia transforms the bone marrow environment and makes it easier for cancer cells to survive. Through innovative technologies like CRISPR-nanobodies and the bone marrow-on-chip, we are investigating the plasticity of endothelial cells and how they might be stopped from aiding leukaemia cells.

PLASTECITY represents a significant shift from simply targeting cancer cells themselves to targeting the environments that support them. With this approach, we hope to make AML treatments not only more effective but also kinder on patients. This could be the first step toward transforming how we approach leukaemia and other aggressive cancers, leading us to a future where relapse and resistance to treatment are no longer a given.

PROJECT NAME

PLASTECITY

PROJECT SUMMARY

PLASTECITY explores how acute leukaemia alters bone marrow endothelial cells, boosting their plasticity to support leukaemia progression. Using genetic tracing, multi OMICs, innovative treatments and tissue bioengineering techniques, it aims to identify and target key genes driving these changes. This approach seeks to disrupt leukaemia-supportive microenvironments, reduce relapse rates, and improve treatments with innovative, patient-tailored strategies.

PROJECT LEAD

Diana Passaro is the group leader of the “Leukemia and Niche Dynamics” team at Institut Cochin, where she explores the pathogenesis of acute leukaemia and its interaction with the surrounding microenvironment. Initially trained in leukaemia stem cell biology, she quickly developed an interest in the way leukaemia interact with and alter the bone marrow niche to promote disease progression and resistance to therapy. During her career, Diana has made notable contributions to the field of bone marrow imaging and bioengineering, developing innovative models and techniques to improve the way we study complex cellular behaviours and interactions. Her independent research laboratory has been recently established with support from various national and international funding sources, including a recently awarded ERC StG. Besides her commitment to mentoring the next generation of researchers through PhD supervision and teaching/ training activities, Diana is actively involved in the scientific direction of the Cochin imaging platform and the IdEx FORMULA programme to foster collaborative research excellence. Her contribution to science dissemination as an invited speaker at conferences and with clinical valorisation efforts shows her strong commitment to translating her team’s discoveries into novel diagnostic and therapeutic strategies and improving leukaemia treatment outcomes.

PROJECT CONTACT

Diana Passaro

Email: diana.passaro@inserm.fr
Web: https://institutcochin.fr/en/equipes/leukemia- and-niche-dynamics
X: @DoctorDianaP
Bluesky: @DoctorDianaP

FUNDING

This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 101116663.