Biology subjects

Hull, S.

Publications and source records attributed to Hull, S..

3 recordsLinked to original sources

bioRxiv2025

Cooperativity between Ras pathway mutations in colonic tumorigenesis

The Kirsten rat sarcoma (KRAS) gene is the most frequently mutated oncogene in colorectal cancer (CRC). We previously characterized two activating alleles of KRAS, A59T and A59E, that show impaired BRAF dimerization. These alleles of KRAS are enriched in CRC tumors with genetic alterations in genes that regulate MAPK signaling (e.g. EGFR, NF1). Using a new conditional mouse model of K-Ras (LSL-K-Ras A59E) we show that, despite its inability to universally activate RAF kinases, K-Ras A59E disturbs colon epithelium and decreases mouse survival in a tumor model. By combining LSL-K-Ras A59E mice with a conditional knockout of Nf1, we demonstrate cooperation between these alleles at multiple levels. Consistent with cooperation and clinical observations, we show that K-Ras A59E neither promotes EGF independence of organoid growth, nor confers intrinsic resistance to EGFR inhibition. Thus, our data provide a deeper understanding of the role of RAF isoforms in mutant KRAS driven CRC and argue for the use of anti-EGFR therapies against some Ala59 mutant alleles of KRAS. Statement of significanceOur studies on oncogenic K-RAS mutants demonstrate that the biochemical properties of a mutant oncoprotein are reflected in the somatic genetics of cancer, in particular in the cooperating mutations that occur. These mutant-specific genetic interactions influence therapeutic responses. As such, KRAS mutation may not be a univariate predictor of response to EGFR inhibition.

cancer biology↗

bioRxiv2025

Baseline expression of c-Myc defines the tissue specificity of oncogenic K-Ras

KRAS is among the most frequently mutated oncogenes in cancer. Yet, mutations in KRAS are common only in tumors originating from a subset of tissues. It is critical to understand the molecular mechanisms underlying this oncogene tissue specificity. Utilizing genetically engineered mouse models carrying a conditional oncogenic allele of Kras, we expressed activated K-Ras in adult tissues to investigate its specificity. We discovered that the ability of K-RasG12D to influence the fitness of cells in a given tissue is not determined by its canonical signaling through MAPK. Instead, low baseline expression of c-Myc renders tissues non-permissive to oncogenic K-Ras, a context that can be reversed in the liver by ectopically expressing c-Myc. This functions independently of the proliferative index of the tissue or the induction of cell cycle arrest or apoptosis. Our findings reveal the importance of the basal state of the tissue-inherent signaling network for determining oncogene specificity.

cancer biology↗

bioRxiv2023

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

neuroscience↗