Biology subjects

Martin, C. P.

Publications and source records attributed to Martin, C. P..

5 recordsLinked to original sources

bioRxiv2026

PPARα-dependent effects in the liver and jejunum of mice in response to pemafibrate

Peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that plays a central role in metabolic adaptation by regulating gene expression programs involved in lipid utilization and energy homeostasis. Although the hepatic functions of PPAR and its target genes are well characterized, less is known about its transcriptional activity in extrahepatic tissues. Pemafibrate (K-877), a selective PPAR modulator (SPPARM), is a high-affinity PPAR ligand with improved potency and selectivity compared with conventional fibrates. Here, we investigated pemafibrate-induced tissue-specific transcriptional responses comparing wild type and whole-body PPAR-deficient littermate mice. Twelve-week-old male PPAR+/+ and PPAR-/- mice were treated daily with pemafibrate (0.1 mg/kg) or vehicle by oral gavage for 14 days. We performed genome-wide transcriptomic analyses in the liver, jejunum, kidney, soleus muscle, and BAT. Pemafibrate-induced transcriptional changes were entirely dependent on PPAR, as no differentially expressed genes were detected in PPAR-/- mice. The magnitude and nature of the response were tissue-specific, with the strongest transcriptional effects observed in the liver and jejunum, whereas the kidney, soleus muscle, and BAT showed limited responses. In the liver, pemafibrate primarily induced the expression of genes involved in fatty acid metabolism, mitochondrial function, and energy production. In the jejunum, pemafibrate activated lipid metabolic programs together with tissue-specific pathways related to cellular homeostasis. Collectively, our findings show that pemafibrate is a highly selective PPAR activator with a preferential transcriptional activity in the liver and intestine after oral administration. This study provides a resource for defining tissue-specific PPAR-responsive gene networks and expands our understanding of PPAR functions beyond the liver.

pharmacology and toxicology↗

bioRxiv2025

p53 and YAP/TAZ-TEAD activities determine metaplastic heterogeneity in pancreatic cancer

BACKGROUND and AIMSPancreatic ductal adenocarcinoma (PDAC) initiation and progression is characterized by lineage plasticity across a continuum of metaplastic and malignant cell fates. This molecular heterogeneity influences disease progression and therapeutic response, yet the genetic and molecular interactions underlying cellular plasticity during PDAC progression remain poorly understood. Here we studied how p53, the most frequently inactivated tumor suppressor in PDAC, interacts with the YAP/TAZ-TEAD transcriptional effector arm of the Hippo pathway to determine cell fate and neoplastic heterogeneity in PDAC development. METHODSWe characterized differentiation states in mouse PDAC and pre-malignant cells in response to p53 activation or inactivation, respectively, and upon genetic, pharmacological, and physiological modulation of YAP/TAZ-TEAD activity. Differentiation was analyzed in vivo in an orthotopic PDAC model permitting independent, inducible control of p53 and TEAD function. We analyzed the effect of p53 and YAP/TAZ-TEAD activity on cell fate in mouse and human PDAC and analyzed markers of clinically relevant molecular subtypes in human PDAC cell lines treated with small molecule TEAD inhibitors. RESULTSRe-engaging wildtype p53 function in KrasMut pancreatic cancer cells increases TEAD activity through accumulation of its co-activator TAZ. Remarkably, increased YAP/TAZ-TEAD activity broadly suppresses the expression of overlapping markers of gastric pit-like (GPL) differentiation and the classical PDAC subtype that are promoted by p53. Accordingly, p53 and YAP/TAZ-TEAD activity inversely correlate with GPL and classical differentiation during PDAC development and modulation of both pathways determines expression of GPL and classical markers in vitro and in vivo. GPL differentiation is acutely sensitive to YAP/TAZ-TEAD activity including oncogenic perturbations of the Hippo pathway, actin dynamics, cell-to-cell contact, and adaptative YAP/TAZ accumulation in response to Ras/MAPK pathway inhibition. Functional repression of gastric-classical differentiation by TEAD persists in human PDAC where potent TEAD inhibition increases expression of GPL and classical markers. CONCLUSIONSWe find that p53 and YAP/TAZ-TEAD activities determine gastric plasticity during PDAC development highlighting the role that key cancer drivers and therapeutically targetable signaling pathways play in active maintenance of cellular identity during pancreatic cancer development.

cancer biology↗

bioRxiv2025

p53 activity licenses transcriptional regulation by YAP/TAZ-TEAD to shape expression landscapes during tumorigenesis

The tumor suppressor p53 is the most frequently disabled gene in cancer, where its inactivation promotes the transition between transcriptionally distinct pre-malignant and malignant disease. How p53 action shapes these stage-dependent expression landscapes is poorly understood. Using a mouse model where p53 function is restored in advanced pancreatic cancer, we demonstrate that p53 dependent gene expression is determined by regulation of YAP/TAZ-TEAD transcriptional complexes at multiple levels of molecular control. Restoration of p53 activity in pancreatic cancer cells expands transcriptional regulation by reorganizing TEAD binding at newly accessible enhancer landscapes, resulting in distinct TEAD-driven gene regulatory networks when p53 is inactivated versus engaged. Furthermore, p53 potentiates expression of newly licensed TEAD targets by increasing TAZ levels in response to the actin remodeling associated with cell cycle arrest and senescence. Thus, p53 activity controls the qualitative and quantitative output of YAP/TAZ-TEAD, including secretory programs involved in tumor-immune communication and remodeling of the microenvironment. Our work nominates regulation of YAP/TAZ-TEAD via p53 as a mechanism that determines stage dependent transcriptional landscapes during stepwise tumorigenesis.

cancer biology↗

bioRxiv2024

Mutant IDH uncouples p53 from target gene regulation to disable tumor suppression

p53 prevents tumor initiation and progression via transcriptional regulation of target gene networks. Here, we find that cancer-associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes the outgrowth of cancer cells with transcriptionally active, wild-type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG)-dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression, resulting in disabled upregulation of targets that execute tumor suppression. Specifically, mutant IDH disrupts the expression of pro-apoptotic p53 targets that enable p53-dependent tumor regressions, including the death ligand receptor Fas. Pharmacological inhibition of mutant IDH in TP53 wild-type cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy-induced apoptosis. Therefore, we implicate the disruption of p53 target gene regulation as a reversible, oncogenic feature of cancer-associated IDH mutations. SIGNIFICANCEWe find that chromatin states altered by cancer-associated IDH mutations intersect with transcriptional regulation of p53 target genes. This reversible interaction may represent a strategy to reinvigorate latent tumor suppression in IDH mutant, p53 wild-type tumors.

cancer biology↗

bioRxiv2022

HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

Endosomal Sorting Complexes Required for Transport (ESCRTs) drive reverse topology membrane remodeling events including the formation of intralumenal vesicles within multivesicular bodies, the budding of retroviruses from the plasma membrane, and the scission of the cytokinetic bridge. It has been difficult to study the physiological relevance of this machinery in mammals because many contributing components are essential for viability. To bypass this problem we used combinations of knockout (-), hypomorphic (H) and wildtype (+) alleles to generate a series of mice with a gradual reduction of HD-PTP (product of PTPN23), an ESCRT-associated protein known to cause embryonic lethality when fully depleted. Whereas PTPN23-/H mice died shortly after birth, PTPN23H/H mice developed into adulthood but had reduced size, lipodystrophy, and shortened lifespan. Analysis of 14-day inguinal adipose tissue indicated reduced expression of adipogenesis markers, and PTPN23 knockout preadipocytes similarly display reduced adipogenesis in vitro. Defects in insulin-stimulated signaling were apparent in differentiated PTPN23 knockout adipocytes and PTPN23H/H inguinal adipose tissue in vitro, correlating with reduced levels of insulin signaling hallmarks observed in adult PTPN23H/H inguinal adipose tissue in vivo. Whereas the ESCRT machinery have been suggested to downregulate signaling, these results indicate that HD-PTP promotes insulin-induced signaling in, as well as differentiation of, inguinal adipose tissue. These results revealed unexpected roles for HD-PTP in promoting fat accumulation in mammalian cells through supporting insulin signaling, adipogenesis, and lipid droplet formation.

cell biology↗