PT - JOURNAL ARTICLE AU - Hockney, Sean AU - Parker, Jess AU - Tzivelekis, Babis AU - Helen, Blair AU - Dalgarno, Kenny AU - Pal, Deepali TI - A synthetic human bone marrow extracellular matrix identifies tunnelling nanotubules as druggable mediators of functional cancer-niche crosstalk AID - 10.1101/2023.06.20.545732 DP - 2024 Jan 01 TA - bioRxiv PG - 2023.06.20.545732 4099 - http://biorxiv.org/content/early/2024/07/31/2023.06.20.545732.short 4100 - http://biorxiv.org/content/early/2024/07/31/2023.06.20.545732.full AB - Treatment resistance, conferred onto cancer cells largely by the oncogenic niche, remains a clinically unmet need in leukaemia. Tractable and clinically translatable models that mimic leukaemia-niche crosstalk remain limited, consequently means of clinically drugging microenvironment-driven cancer treatment resistance remain underexplored. Here we develop a prototype bone marrow (BM) like extracellular matrix (ECM), Vitronectin-Alginate-Laminin (VAL), which comprises animal free components, displays viscoelastic properties like the human BM, and engrafts a range of patient-derived-xenograft acute lymphoblastic leukaemia (PDX-ALL) samples. We reveal that VAL-primed PDX-ALL upregulate the mesenchymal gene CDH2, which encodes N-Cadherin. We further show engraftment and long-term proliferation of a range of PDX-ALL samples within VAL-human induced pluripotent stem cell-derived mesenchymal stem cells(iMSC)-organoids, and find that ALL-interactions with both BM-ECM-like VAL and iMSC impact leukaemia treatment response. We confirm tractability of our model to study leukaemia-ECM-MSC crosstalk and discover that following treatment with oxidative stress-inducing apoptotic therapies, such as dexamethasone, ABT-199 and dexamethasone-ABT-199 combination, PDX-ALL cells reach out to MSC via the formation of tunnelling nanotubes (TNT). Nevertheless, we reveal that ALL-VAL-MSC-TNTs are clinically druggable, as they are absent following treatment with CDH2 antagonist ADH-1, a compound well-tolerated in solid cancer Phase I trials. We ultimately reveal a triple drug combination of dexamethasone-ABT-199 and ADH-1, with most synergy area (MSA) scores of >30, that shows high efficacy and disrupts functional cancer-niche-TNTs in 4 different high risk PDX-ALL samples. In summary, here we develop prototype cancer-ECM-niche organoids and using leukaemia as a disease paradigm, we provide proof-of-concept insights enabling the beginning of research into drugging functional cancer cell crosstalk with its surrounding cellular and ECM niche.Competing Interest StatementThe authors have declared no competing interest.