Leukemia Propagating Cells Rebuild An Evolving Niche In Response To Therapy

It is the critical cause of tumor recurrence that cancer stem cells (CSCs) cannotbe effectively eliminated by chemotherapeutic drugs. Previous studies mainly focusedon the intrinsic mechanisms of CSCs, including the expression of drug resistance gene,the state of quiescent, the epigenetic change, and the acquisition of genetic diversityin sub-population and so on. In recent years, the extrinsic mechanisms (or tumormicroenvironment) were initially studied, which indicated the tumormicroenvironment provides a―refuge‖for residual CSCs to escape the damage ofchemotherapy. However, the nature of niches involved and the mechanisms protectingCPCs remain largely unknown.Based on our newly established ex vivo imaging technology combined withtraditional immune-staining, in this study we use xenograft models of human acutelymphoblastic leukemia to find that the infiltration of transplanted leukemic cellsgradually altered the structure of the normal bone marrow microenvironment, anddestroyed the vascular niche and the endosteal niche.Mouse model in two time points was then selected for chemotherapy:1.Infiltration of leukemic cells did not yet destroy the normal niche (Day6model), afterchemotherapy for two or four days, the residual leukemic cells were located in both ofthe vascular niche and the endosteal niche;2. Infiltration of leukemic cells completelydestructed the normal niche (Day12model), after chemotherapy for two or four days,the residual leukemic cells were surrounded by sheaths of supporting cells thatcomprise a novel niche. The cellular components of the novel niche were identified invivo or in vitro experiments after chemotherapy, and found that the niche wasdynamically transient: beginning with Nestin-positive cells, maturating through theirtransition to α-SMA-positive cells, and ending with reticulin fiber residues. Hereafter,the niche is termed as NSM niche. Mechanistically, leukemic cells secrete cytokines to recruit mesenchymal cells and build the novel niche in response to chemotherapy.Furthermore, the NSM niche is neither to produce a physical barrier preventingdrug effectively delivery to the residual leukemic cells, nor to keep the residualleukemic cells being quiescent. Interestingly, the growth and differentiation factor15(GDF15) secreted by the residual cells after chemotherapy mediated the protectiveeffect between NSM niche and its resident cells by activating TGF-β-Smad3signalingpathway. Intervention in the expression or function of GDF15facilitated the removalof NSM niche-resident leukemic cells and longed the survival time of leukemia miceby cytotoxic agents.Clinically, the NSM niche was induced in xenograft mouse models of primaryleukemia patient’ bone marrow after chemotherapy, and the propagation of residualleukemia cells could be detected in secondary and tertiary recipients, demonstratingthat the NSM niche-resident cells were leukemia propagating cells (LPCs). Excitingly,we found direct evidence of the existence of NSM niche in leukemia patient’s bonemarrow biopsy sections, which only exists in the cases of partial or non-remissionafter chemotherapy. Thus, these data suggested that NSM niche formation wasassociated with more difficulties to achieve complete remission after chemotherapy.In summary, our study for the first time found that LPCs (or CSCs) created adynamic evolving niche for preventing the damage of initial chemotherapy.