Biology subjects

Cappell, S. D.

Publications and source records attributed to Cappell, S. D..

5 recordsLinked to original sources

bioRxiv2024

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by MAP3K13) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified MAP3K13. A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules. Inhibition of LZK catalytic activity suppressed tumor growth in HNSCC PDX models with amplified MAP3K13. We found that the kinase activity of LZK stabilized c-MYC and that LZK stabilized gain-of-function (GOF) p53 through a kinase-independent mechanism. Therefore, we designed proteolysis-targeting chimeras (PROTACs) and demonstrate that our lead PROTAC promotes LZK degradation and suppresses expression of GOF p53 and c-MYC leading to impaired viability of HNSCC cell lines. This research provides a strong basis for development of therapeutics targeting LZK in HNSCCs with amplification of the gene. One Sentence SummaryThis study establishes the kinase LZK as a therapeutic target for HNSCC through regulation of c-MYC expression.

cancer biology↗

bioRxiv2024

Lineage-specific CDK activity dynamics characterize early mammalian development

Cyclin-dependent kinases (CDK) are key regulatory enzymes that regulate proliferation dynamics and cell fate in response to extracellular inputs. It remains largely unknown how CDK activity fluctuates and influences cell commitment in vivo during early mammalian development. Here, we generated a transgenic mouse model expressing a CDK kinase translocation reporter (KTR) that enabled quantification of CDK activity in live single cells. By examining pre- and post- implantation mouse embryos at different stages, we observed a progressive decrease in CDK activity in cells from the trophectoderm (TE) prior to implantation. This drop correlated with the establishment of an FGF4-dependent signaling gradient through the embryonic-abembryonic axis. Furthermore, we showed that CDK activity levels do not determine cell fate decisions during pre-implantation development. Finally, we uncovered the existence of conserved regulatory mechanisms in mammals by revealing lineage-specific regulation of CDK activity in TE-like human cells.

developmental biology↗

bioRxiv2023

Comprehensive mapping of cell fates in microsatellite unstable cancer cells support dual targeting of WRN and ATR

Addiction to the WRN helicase is a unique vulnerability of human cancers with high levels of microsatellite instability (MSI-H). However, while prolonged loss of WRN ultimately leads to cell death, little is known about how MSI-H cancers initially respond to acute loss of WRN, knowledge that would be helpful for informing clinical development of WRN-targeting therapy, predicting possible resistance mechanisms, and identifying useful biomarkers of successful WRN inhibition. Here, we report the construction of an inducible ligand-mediated degradation system wherein the stability of endogenous WRN protein can be rapidly and specifically tuned, enabling us to track the complete sequence of cellular events elicited by acute loss of WRN function. We find that WRN degradation leads to immediate accrual of DNA damage in a replication-dependent manner that curiously did not robustly engage checkpoint mechanisms to halt DNA synthesis. As a result, WRN-degraded MSI-H cancer cells accumulate DNA damage across multiple replicative cycles and undergo successive rounds of increasingly aberrant mitoses, ultimately triggering cell death. Of potential therapeutic importance, we find no evidence of any generalized mechanism by which MSI-H cancers could adapt to near-complete loss of WRN. However, under conditions of partial WRN degradation, addition of low dose ATR inhibitor significantly increased their combined efficacy to levels approaching full inactivation of WRN. Overall, our results provided the first comprehensive view of molecular events linking upstream inhibition of WRN to subsequent cell death and suggested a potential therapeutical rationale for dual targeting of WRN and ATR.

cancer biology↗

bioRxiv2020

Targeting nuclear pore protein, NUP210, reduces metastasis through heterochromatin-mediated silencing of mechanosensitive genes

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identified nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides a new insight into the role of nuclear pore protein in cellular mechanosensation and metastasis.

cancer biology↗

bioRxiv2019

Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation

U2AF1 forms a heterodimeric complex with U2AF2 that is primarily responsible for 3 splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome and Acute Myeloid Leukemia, and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). However, the U2AF heterodimer also has a non-canonical function as a translational regulator. Here, we report that the U2AF1 S34F mutation results in specific mis-regulation of the translation initiation and ribosome biogenesis machinery, with the potential for widespread translational changes. The net result is a global increase in mRNA translation at the single cell level. Among the translationally upregulated targets of U2AF1-S34F are Nucleophosmin1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of wt/S34F cells and causes rRNA processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1 and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation which recapitulates translational mis-regulation in myeloid disease.

cell biology↗