A genome-wide single-cell 3D genome atlas of lung cancer progression.

Alterations in three-dimensional (3D) genome structures are associated with cancer1-5. However, how genome folding evolves and diversifies during subclonal cancer progression in the native tissue environment remains unknown. Here, we leveraged a genome-wide chromatin tracing technology to directly visualize 3D genome folding in situ in a faithful Kras-driven mouse model of lung adenocarcinoma (LUAD)6, generating the first single-cell 3D genome atlas of any cancer. We discovered stereotypical 3D genome alterations during cancer development, including a striking structural bottleneck in preinvasive adenomas prior to progression to LUAD, indicating a stringent selection on the 3D genome early in cancer progression. We further showed that the 3D genome precisely encodes cancer states in single cells, despite considerable cell-to-cell heterogeneity. Finally, evolutionary changes in 3D genome compartmentalization - partially regulated by polycomb group protein Rnf2 through its ubiquitin ligase-independent activity - reveal novel genetic drivers and suppressors of LUAD progression. Our results demonstrate the importance of mapping the single-cell cancer 3D genome and the potential to identify new diagnostic and therapeutic biomarkers from 3D genomic architectures.

Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.

Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.

A foretaste for pediatric glioblastoma therapy: targeting the NF-kB pathway with DHMEQ.

PURPOSE: While pediatric glioblastomas are molecularly distinct from adult counterparts, the activation of NF-kB is partially shared by both subsets, playing key roles in tumor propagation and treatment response. RESULTS: We show that, in vitro, dehydroxymethylepoxyquinomicin (DHMEQ) impairs growth and invasiveness. Xenograft response to the drug alone varied according to the model, being more effective in KNS42-derived tumors. In combination, SF188-derived tumors were more sensitive to temozolomide while KNS42-derived tumors responded better to the combination with radiotherapy, with continued tumor regression. CONCLUSION: Taken together, our results strengthen the potential usefulness of NF-kB inhibition in future therapeutic strategies to overcome this incurable disease.