Multivariate modeling of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.

Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges in identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tissue lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings using data from an independent set of cell lines, pharmacological screens, and via single-cell analysis of patient-derived tumors. Our analysis uncovers new synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating these relationships could inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

Loss of NF1 in Melanoma Confers Sensitivity to SYK Kinase Inhibition.

Neurofibromin 1 (NF1) loss of function (LoF) mutations are frequent in melanoma and drive hyperactivated RAS and tumor growth. NF1LoF melanoma cells, however, do not show consistent sensitivity to individual MEK, ERK, or PI3K/mTOR inhibitors. To identify more effective therapeutic strategies for treating NF1LoF melanoma, we performed a targeted kinase inhibitor screen. A tool compound named MTX-216 was highly effective in blocking NF1LoF melanoma growth in vitro and in vivo. Single-cell analysis indicated that drug-induced cytotoxicity was linked to effective cosuppression of proliferation marker Ki-67 and ribosomal protein S6 phosphorylation. The antitumor efficacy of MTX-216 was dependent on its ability to inhibit not only PI3K, its nominal target, but also SYK. MTX-216 suppressed expression of a group of genes that regulate mitochondrial electron transport chain and are associated with poor survival in patients with NF1LoF melanoma. Furthermore, combinations of inhibitors targeting either MEK or PI3K/mTOR with an independent SYK kinase inhibitor or SYK knockdown reduced the growth of NF1LoF melanoma cells. These studies provide a path to exploit SYK dependency to selectively target NF1LoF melanoma cells. SIGNIFICANCE: A kinase inhibitor screen identifies SYK as a targetable vulnerability in melanoma cells with NF1 loss of function.

Functionalizing Fibrin Hydrogels with Thermally Responsive Oligonucleotide Tethers for On-Demand Delivery.

There are a limited number of stimuli-responsive biomaterials that are capable of delivering customizable dosages of a therapeutic at a specific location and time. This is especially true in tissue engineering and regenerative medicine applications, where it may be desirable for the stimuli-responsive biomaterial to also serve as a scaffolding material. Therefore, the purpose of this study was to engineer a traditionally non-stimuli responsive scaffold biomaterial to be thermally responsive so it could be used for on-demand drug delivery applications. Fibrin hydrogels are frequently used for tissue engineering and regenerative medicine applications, and they were functionalized with thermally labile oligonucleotide tethers using peptides from substrates for factor XIII (FXIII). The alpha 2-plasmin inhibitor peptide had the greatest incorporation efficiency out of the FXIII substrate peptides studied, and conjugates of the peptide and oligonucleotide tethers were successfully incorporated into fibrin hydrogels via enzymatic activity. Single-strand complement oligo with either a fluorophore model drug or platelet-derived growth factor-BB (PDGF-BB) could be released on demand via temperature increases. These results demonstrate a strategy that can be used to functionalize traditionally non-stimuli responsive biomaterials suitable for on-demand drug delivery systems (DDS).

Effects of Methacrylate-Based Thermoresponsive Polymer Brush Composition on Fibroblast Adhesion and Morphology.

Thermoresponsive polymers are being used increasingly in cell culture applications due to their temperature dependent surface properties. Poly(MEO2MA-co-OEGMA) (PMO) brushes offer tunable physical properties via variation in the copolymer ratio, but the effects of composition on cell-substrate interactions is unclear. To this end, a series of PMO brushes (0-8% OEGMA) was fabricated and L-929 fibroblast adhesion and morphology was quantified in the presence of serum (FBS) or after functionalization via the adsorption of fibronectin (FN) and vitronectin (VN). Quantification of the adsorption of model proteins, bovine serum albumin and FN, revealed that the extent of adsorption was correlated to the amount MEO2MA content, which represents the more hydrophobic component in PMO brushes. Cells exhibited delayed attachment and spreading on all PMO substrates in the presence of FBS. After 24 h, cell attachment was comparable; however, increased spreading was correlated with increased MEO2MA content. Adsorption of FN significantly increased initial cell attachment to all PMO surfaces after 2 h. This was not observed with VN; however, both FN and VN increased cell spreading/decreased cell circularity for all PMO substrates relative to FBS. Pure MEO2MA brushes with FN exhibited increased cell spreading/decreased cell circularity relative to other PMO substrates after 2 h, and elicited the highest cell density after 24 h. These results demonstrate that increased MEO2MA content in PMO substrates facilitates cell attachment and spreading, which can be further enhanced by adsorbing FN in the absence of other proteins.