Biology subjects

Tremblay, J. R.

Publications and source records attributed to Tremblay, J. R..

3 recordsLinked to original sources

bioRxiv2026

H3 dopaminylation and CaMKII modulate diffuse midline glioma response to CDK9 inhibition

Aberrant neurotransmitter signaling and transcriptional dysregulation are hallmarks of gliomagenesis and represent potential therapeutic targets. Monoamine neurotransmitters such as dopamine and serotonin primarily activate GPCRs but can also function epigenetically as histone H3 modifications. Here, we uncover mechanisms of crosstalk between monoamine neurotransmitter signaling, H3 dopaminylation, and RNA polymerase II (Pol2) transcription in diffuse midline glioma (DMG). We find that co-treatment with Pol2-targeting CDK9 inhibitors (CDK9i) and FDA-approved neuropsychiatric drugs, including selective serotonin reuptake inhibitors (SSRIs), synergistically reduces DMG growth. Mechanistically, CDK9i+SSRI treatment alters H3 dopaminylation patterns and represses synaptic and neurodevelopmental gene transcription associated with CDK9i resistance. Further phospho-proteomic analyses show that CDK9i monotherapy activates pro-survival CaMKII signaling, which can be suppressed by co-treatment with neuromodulatory drugs. These studies establish roles for H3 dopaminylation and neurotransmitter signaling in DMG gene regulation and response to CDK9i, suggesting that monoamine neurotransmitter pathways may be exploited as a therapeutic strategy for DMG.

cancer biology↗

bioRxiv2026

CA19-9 promotes liver metastasis of pancreatic cancer through E-selectin mediated extravasation

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes to the liver, which drives patient mortality. CA19-9 is elevated in most PDAC tumors and is widely used as a clinical biomarker. Elevated serum levels are associated with poor outcomes. However, whether CA19-9 functionally contributes to metastatic progression has not been fully defined, in part because mice lack endogenous CA19-9 expression. Here, using syngeneic murine PDAC cells engineered to express CA19-9, we investigated its functional role in liver metastasis. In splenic injection models, CA19-9 expression markedly increased liver metastatic burden by promoting both metastatic seeding and subsequent metastatic outgrowth. In vitro, CA19-9 enhanced tumor cell adhesion to endothelial cells through interaction with E-selectin. Metastatic seeding of CA19-9-expressing cells was reduced by genetic deletion of E-selectin or antibody neutralization of either CA19-9 or E-selectin in vivo. Therapeutic targeting of CA19-9 with a neutralizing antibody markedly reduced liver metastatic burden after metastatic seeding. CA19-9 expression increased AKT signaling in PDAC cells and liver metastases, and CA19-9 levels correlated with AKT activation in human PDAC tissues. These findings show that CA19-9 promotes PDAC liver metastasis through E-selectin-dependent metastatic seeding and AKT-associated metastatic outgrowth, highlighting CA19-9 as a functional mediator of PDAC metastasis and a potential therapeutic target.

cancer biology↗

bioRxiv2022

Identification of a distinct ductal subpopulation with self-renewal and differentiation potential from the adult murine pancreas

Pancreatic ducts function to deliver digestive enzymes into the intestines. Upon injury, ducts can become proliferative and contribute to tissue regeneration; however, the identity of the ductal cells that contribute to these processes is unknown. We combined fluorescence-activated cell sorting, a methylcellulose-containing 3-dimensional culture, droplet RNA-sequencing, and a clonal lineage tracing tool to identify and isolate a distinct subpopulation of pancreatic ductal cells that exhibit progenitor cell properties. These ductal cells are unique in that they form tightly-bound clusters (termed FSCmid-high), with an average of 8 cells per cluster. FSCmid-high clusters comprise only about 0.1% of the total pancreas, are tri-potent for duct, acinar and endocrine lineages, and self-renew robustly in vitro. Transcriptomic analysis of FSCmid-high clusters reveals enrichment for genes involved in cell-cell interactions, organ development, and cancer pathways. FSCmid-high clusters express embryonic pancreatic progenitor markers Sox9, Pdx1, and Nkx6-1 at both transcription and protein levels. FSCmid-high clusters are resistant to enzymatic dissociation and survive severe in vivo acinar injury, which induces formation of ductal rosettes that become proliferative within 14 days. Thus, FSCmid-high clusters represent a small subset of ductal cells with progenitor cell properties. These rare progenitor-like duct cell clusters have implications in pancreas regeneration and tumor initiation/progression.

cell biology↗