Abstract
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 Statement
The authors have declared no competing interest.
Footnotes
Data has been updated largely to figures 3-5. Additional methods and details have been incorporated Supplementary data has been included. The abstract and discussion has been updated to reflect the changes. Corresponding authors email address and affiliation has been updated
