Lab News [follow us on twitter: https://twitter.com/3RsLabPal ] 

Key publications:

1. Human iPSC-engineered bone marrow niche constituents:  hiPSC-derived bone marrow milieu identifies a clinically actionable driver of niche-mediated treatment resistance in leukemia 

Preview: Regenerative medicine meets translational oncology: Modeling leukemic bone marrow niche

Lay Summary: Scientists step closer to low toxicity treatment for childhood cancer

2. Development of human-cell-based MSC-ALL spheroid models with high in vivo predictivity :  A human mesenchymal spheroid prototype to replace moderate severity animal procedures in leukaemia drug testing

Active projects, externally funded:

3D bioprinted microtissues to develop patient-specific non-animal technologies (NAT) in cancer drug development

Assessment of an in vitro acute lymphoblastic leukaemia model for high-throughput arrayed CRISPR screening  Utilising the technology developed by Dr Deepali Pal, this project was awarded £42,268, aiming to identify gene pathways by which leukaemia cells interact with bone marrow cells, and how these interactions might contribute to drug resistance. 

We are very grateful to our funders for supporting our research:

1. NC3RS PhD Studentship award, principal investigator, 2021-2024: £90,000

Project: https://nc3rs.org.uk/our-portfolio/3d-bioprinted-microtissues-develop-patient-specific-non-animal-technologies-nat

2. NC3Rs T2T scheme, academic principal investigator, 2023-2024

Project: Assessment of an in vitro acute lymphoblastic leukaemia model for high-throughput arrayed CRISPR screening 

3. NC3Rs Fellowship, principal investogator, 2017-2019: £112,473, 

Project: https://www.nc3rs.org.uk/our-portfolio/industrial-standard-cancer-drug-development-platform-using-human-induced-pluripotent

4. Children’s Cancer and Leukaemia Group, The Little Princess Trust Project Grant, principal investigator, 2016-2018: £99,991.60.

Project: Finding a new drug to treat B-cell acute lymphoblastic leukaemia (ALL) https://www.cclg.org.uk/write/MediaUploads/Research/Impact%20report/415_CCLG-Research-Impact-Report-Download.pdf

5. JGW Patterson Foundation fellowship, principal investigator, 2016-2017: £49,508.27. 

Research Expertise: Cancer research, Malignant bone marrow microenvironment, Regenerative Medicine, Human Development, Stem Cells, Medical Sciences: anatomy, physiology, internal medicine [haematooncology, regenerative medicine and transplant, precision medicine], general surgery [urology, orthopaedics]

Affiliations: Associate Lecturer, Northern Institute for Cancer Research, Newcastle University. 

Biography: 

My vision is to develop safer and kinder, chemotherapy-free and biology-driven treatments for childhood leukaemia.

My research strategy is to integrate basic biology and translational research with engineering and physical sciences, and develop transformative research technologies and preclinical models, to drive breakthrough discoveries that postively impact patient outcome.

I have two research goals: 1. Discovery of new mechanisms and cell-cell crosstalk that drive cancer biology within the context of its microenvironment, and consequently discovery of clinically actionable targets in childhood leukaemia 2. Development of transformative research technologies, preclinical models and methods to enable clinically relevant research and breakthrough biological discoveries.

I lead an interdisciplinary research group driving hypothesis-driven projects of significant translational relevance.  My research group focuses on engineering anatomically precise and clinically relevant microtissues through 3D bioprinting. Our expertise encompasses stem cells [induced pluripotent stem cells, stem cell reprogramming, mesenchymal stem cells, other adult stem cells], tissue engineering [organoids, 3D biorpinted microtissues], exploring mechanistics of cancer-microenviornment interactions and hypothesis-driven target discovery identifying novel drug combination strategies in leukaemia. 

I  have over a decade's experience as staff researcher in academia. Following my medical training [Manipal University, India], I obtained an international EU FP7 Marie Curie Fellowship to pursue my doctoral research in human development and regenerative medicine.  Subsequently, in line with my postdoctoral research [JGW Patterson Fellow, MRC-NC3Rs Fellow] I established my group in cancer research and regenerative medicine. Our vision is to deliver clinically relevant non-animal technologies/preclinical models towards regenerative medicine and precision medicine.

Research Contributions/Achievements:

• EU FP7 Marie Curie Fellow: 2010
• NC3Rs Fellow: 2017
• NC3Rs Project Grant Assessment Panel member: 2023-2026
• Invited talk at the ISSCR 2024 anual conference: Programme agenda
• Invited speaker at the NC3Rs Oncology Network launch, 2024
• Invited speaker at the CCLG annual conference, 2024
• Invited speaker and chair at Kind Philipp Tagung Conference, Wilsede, Germany, 2019
• Children with Cancer conference, Newcastle, UK, September 2017: Abstract selected as top ten most interesting abstracts for oral presentation. Best talk award at Children with Cancer conference.
• Association pour la Recherche sur les Tumeurs de la Prostate (ARTP, French Organisation for Prostate Cancer Research) award for the best oral presentation in Prostate Cancer Research at the 20th Meeting of the European Association of Urology Section of Urological Research, Strasbourg, October 2013.
• 8th NCRI Cancer Conference, Liverpool, November, 2012. Invited speaker. Abstracts won National Cancer Research Institute Prize award 2012.
• Celebrated female researcher for International Women’s Day, 2018 by NC3Rs: https://www.nc3rs.org.uk/news/celebrating-female-researchers-international-women%E2%80%99s-day-2018
• Invited speaker on current NC3Rs fellowship as an early-career scientist in the North-East, York University research Symposium, November 2017
• Invited by the NC3Rs to write a blog on applying for early career awards, September 2017: https://nc3rs.org.uk/news/applying-early-career-awards  
• Invited speaker at Kind Philipp Tagung Conference, Wilsede, Germany, 2017
• Invited speaker at European school of Haematology 2nd scientific conference on the tumour environment in haematological malignancies and its therapeutic targeting, Berlin, Germany, 2017
• Invited to write a preview article in Cancel Cell [ Journal impact factor: 23.5]
• Pal, D., Heidenreich, O., Vormoor, J. Dormancy stems the tide of chemotherapy. Cancer Cell, November 2016
• Invited speaker at the CLR-UK meeting, Bristol, 2014: Leukaemia research
• Invited speaker at the Academic Urology section of the Annual SARS (Society of Academic and Research Surgery) meeting, 2012.

Lecturing and Scolarship:

I mentor early career researchers and supervise doctoral students. I develop and deliver research-led and student-feedback-led modules and lectures in cancer biology. 

We are keen on hearing from driven and conscientious PhD candidates. We provide mentorship to early career researchers interested in the following research areas. 

MRes Research Projects, X2: link to projects

Induced pluripotent stem cell (iPSC) engineered, immune-responsive bone marrow microenvironment (BME) to develop leukaemia-specific oncogenic niche in vitro:

Human iPSC will be differentiated into CD14+ monocyte-like cells via an intermediate hemogenic endothelial route. CD14+ monocytes will be further differentiated into macrophage cells, which following functional validation will be incorporated into existing multicellular BME organoids (preprint , article). Immune-responsive BME-leukaemia organoid prototypes will be implemented to accelerate target discovery and precision oncology driven cancer drug development.

Targeted drug delivery to CDH2-enriched leukaemic bone marrow microenvironment (BME):

CDH2 encoding the protein N-Cadherin, is associated with increased cancer invasiveness and its upregulation has been observed in human leukaemia bone marrows, and we recently discovered that BME-primed leukaemia cells upregulate CDH2 (article). Moreover, monoclonal antibody targeting of N-Cadherin has been proven to inhibit metastasis and invasion in solid cancers. This project will develop anti-N-Cadherin-functionalised-liposomes encapsulating anti-leukaemia inhibitors to facilitate targeted drug delivery into leukaemia BME.

Research Strategy:

Develop stratified-oncology driven safer and kinder treatments for leukaemia by targetting the cancer niche.

Core Objectives:

1. Novel drug combination strategies in children’s leukemia

Question: Can we identify targetable niche-mediated synthetic lethal interactors and sensitisors against leukemia dormancy and treatment resistance?

Cancer dormancy  and treatment resistance are two key clinical challenges that need urgent attention. Using transformative 3D bioprinted co-culture organoid models, my aim is to define cancer-niche communications, including cancer-immune cell interactions driving treatment response. Specifying the functional role of the oncogenic niche in regulating leukemia viability, proliferation, dormancy and treatment resistance will identify novel synthetic lethal interactors of known oncogenes. This will also reveal drug sensitizers in order to tackle treatment resistance, a key clinical challenge. Our vision is to reveal novel “chemo-free” therapeutic strategies towards Phase I trials.

2. 3Rs compliant, immune-responsive non animal technologies[organoids], paradigm: human bone marrow

Question: Can we engineer faster, better and cheaper synthetic patient-microtissues ex vivo through automation?

Developing a scalable, tractable, multicellular bone marrow is technically challenging and identifying interactions between different cells is best obtained through 3D organoid models that reflect the spatial anatomy of a complex structure with greater precision. This ambition is being made possible through my collaboration with the Department of Engineering, Newcastle University Our vision is to engineer human cell based platforms that capture the spatial anatomy of complex multicellular structures thereby facilitating hypothesis-driven identification and functional validation of therapeutic targets disrupting the cancer-niche interplay.  

3. Regenerative medicine and stem cells, paradigm: human bone and bone marrow

Question: Can we identify aberrations of normal development/ageing towards therapeutic exploitation?

Our aim is to define key processes in human development through differentiation of stem cells as well as de-differentiation of terminal cells to their primitive precursors. This will not only form the basis of tissue engineering but will also reveal key insights into ageing as well as potentially identify targetable aberrations of “normal” development leading to diseases such as cancer.