Diversity in the genetic lesions that cause cancer is extreme. In consequence, a pressing challenge is the development of drugs that target patient-specific disease mechanisms. To address this challenge, we employed a chemistry-first discovery paradigm for de novo identification of druggable targets linked to robust patient selection hypotheses. In particular, a 200,000 compound diversity-oriented chemical library was profiled across a heavily annotated test-bed of >100 cellular models representative of the diverse and characteristic somatic lesions for lung cancer. This approach led to the delineation of 171 chemical-genetic associations, shedding light on the targetability of mechanistic vulnerabilities corresponding to a range of oncogenotypes present in patient populations lacking effective therapy. Chemically addressable addictions to ciliogenesis in TTC21B mutants and GLUT8-dependent serine biosynthesis in KRAS/KEAP1 double mutants are prominent examples. These observations indicate a wealth of actionable opportunities within the complex molecular etiology of cancer.

Dysregulation of DNA methylation and mRNA alternative cleavage and polyadenylation (APA) are both prevalent in cancer and have been studied as independent processes. We discovered a DNA methylation-regulated APA mechanism when we compared genome-wide DNA methylation and polyadenylation site usage between DNA methylation-competent and DNA methylation-deficient cells. Here, we show that removal of DNA methylation enables CTCF binding and recruitment of the cohesin complex, which, in turn, form chromatin loops that promote proximal polyadenylation site usage. In this DNA demethylated context, either deletion of the CTCF binding site or depletion of RAD21 cohesin complex protein can recover distal polyadenylation site usage. Using data from The Cancer Genome Atlas, we authenticated the relationship between DNA methylation and mRNA polyadenylation isoform expression in vivo. This DNA methylation-regulated APA mechanism demonstrates how aberrant DNA methylation impacts transcriptome diversity and highlights the potential sequelae of global DNA methylation inhibition as a cancer treatment.

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Vertically aligned nanomaterials, such as nanowires and nanoneedles, hold strong potential as efficient platforms onto which living cells or tissues can be interfaced for use in advanced biomedical applications. However, their rigid mechanical properties and complex fabrication processes hinder their integration onto flexible, tissue-adaptable, and large-area patch-type scaffolds, limiting their practical applications. In this study, we present a highly flexible patch that possesses a spiky hydrogel nanostructure array as a transplantable platform for enhancing the growth and differentiation of stem cells and efficiently suppressing biofilm formation. In vitro studies show that the hydrogel nanospike patch imposes a strong physical stimulus to the membranes of stem cells and enhances their osteogenic, chondrogenic, and adipogenic differentiation and the secretion of crucial soluble factors without altering cell viability. At the same time, the array exhibits effective bactericidal properties against Gram-positive and Gram-negative bacteria. In vivo studies further demonstrate that the flexible hydrogel patch with its spiky vertical nanostructures significantly promotes the regeneration of damaged cranial bone tissues while suppressing pathogenic bacterial infections in mouse models.