Biology subjects

Berres, M. E.

Publications and source records attributed to Berres, M. E..

2 recordsLinked to original sources

bioRxiv2025

Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning and increases cAMP-PKA signaling in a zebrafish model of Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss of function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor suppressing protein that regulates Ras, cAMP, and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors, and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we identify Cxcr4 chemokine receptor signaling as a regulator of habituation learning and modulator of cAMP-PKA signaling in nf1 mutant larval zebrafish. Combining a small-molecule drug screen and RNAseq analysis, we show that cxcr4b expression is increased in nf1 mutants and that pharmacological inhibition of Cxcr4 with AMD3100 (Plerixafor) improves habituation learning in nf1 mutants. We further demonstrate that Plerixafor treatment activates cAMP-PKA pathway signaling but has limited effects on Ras-Raf-MEK-ERK pathway signaling in the nf1 mutant brain. CXCR4 was previously identified as a potential therapeutic target for neurofibromin-deficient tumorigenesis. Our results provide evidence that Cxcr4 signaling also regulates neurofibromin-dependent cognitive function.

neuroscience↗

bioRxiv2023

CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma

Fibrolamellar carcinoma (FLC) is a rare and lethal cancer that afflicts young individuals. The tumor arises in the background of a healthy liver, and patients typically present with advanced cancer at the time of diagnosis. Unfortunately, for these patients with advanced or recurrent cancer, no proven systemic therapies exist resulting in only 30-45% of patients surviving to 5 years. Investigations into the molecular underpinning of FLC have revealed a unique gene fusion between heat shock protein 40 (DNAJB1) and the catalytic subunit alpha of protein kinase A (PRKACA), leading to the formation of an oncoprotein (DNAJ-PKAc) that retains kinase activity and is a proven tumor-causing event in FLC. To uncover potential therapeutic targets, we engineered an FLC cell line by introducing the DNAJB1-PRKACA oncogene rearrangement into human hepatocellular cells using CRISPR/Cas9. We identified aberrant cell cycle progression, and follow-up molecular analysis revealed evidence of enhanced cyclin dependent kinase 7 (CDK7) activation in the DNAJB1-PRKACA expressing FLC cells. These findings were confirmed in human samples of FLC. In turn, targeting CDK7 with selective inhibitors demonstrated efficacy in several patient-derived models of FLC, with minimal toxicity to normal liver. Collectively, this work uncovers a novel candidate therapeutic vulnerability in FLC.

cancer biology↗