Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I–IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling >4,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.

A vital quest in biology is comprehensible visualization and interpretation of correlation relationships on a genome scale. Such relationships may be represented in the form of networks, which usually require disassembly into smaller manageable units, or clusters, to facilitate interpretation. Several graph-clustering algorithms that may be used to visualize biological networks are available. However, only some of these support weighted edges, and none provides good control of cluster sizes, which is crucial for comprehensible visualization of large networks. We constructed an interactive coexpression network for the Arabidopsis (Arabidopsis thaliana) genome using a novel Heuristic Cluster Chiseling Algorithm (HCCA) that supports weighted edges and that may control average cluster sizes. Comparative clustering analyses demonstrated that the HCCA performed as well as, or better than, the commonly used Markov, MCODE, and k-means clustering algorithms. We mapped MapMan ontology terms onto coexpressed node vicinities of the network, which revealed transcriptional organization of previously unrelated cellular processes. We further explored the predictive power of this network through mutant analyses and identified six new genes that are essential to plant growth. We show that the HCCA-partitioned network constitutes an ideal "cartographic" platform for visualization of correlation networks. This approach rapidly provides network partitions with relative uniform cluster sizes on a genome-scale level and may thus be used for correlation network layouts also for other species.

TCF3-HLF-fusion positive acute lymphoblastic leukemia (ALL) is currently incurable. Employing an integrated approach, we uncovered distinct mutation, gene expression, and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. Recurrent intragenic deletions of PAX5 or VPREB1 were identified in constellation with TCF3-HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin towards a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics, but sensitivity towards glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.

Highlights d Detailed, large-scale mechanistic model of cancer-related signaling pathways d Speedup of over 10,000-fold enables data-driven modeling at unprecedented scales d Pronounced parameter uncertainties do not imply pronounced prediction uncertainties d Mechanistic models can predict response to drug combinations from single drug data