Tunnelling nanotubules are druggable mediators of cancer-niche crosstalk.

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 cancer-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 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 expose 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.