Biology subjects

Nieto Carrion, J. A.

Publications and source records attributed to Nieto Carrion, J. A..

3 recordsLinked to original sources

bioRxiv2025

Glucose Metabolism Sustains Aberrant STAT3 Signaling in Colorectal Cancer via Glycosylated Paracrine Factors.

The JAK-STAT3 signaling pathway is a key driver of colorectal cancer (CRC) progression. While STAT3 is canonically activated by cytokines such as IL-6, this activation is typically transient due to negative feedback mechanisms. In CRC, however, STAT3 is aberrantly and persistently activated, promoting tumor cell proliferation and survival. Here, we demonstrate that glucose sustains STAT3 activation independent of cytokine availability. By manipulating glucose metabolism, we show that both glucose and its downstream metabolite, GlcNAc, are essential for maintaining STAT3 activation. Moreover, cells with high basal STAT3 activity produce glucose-dependent glycosylated proteins that can activate STAT3 in neighboring cells via paracrine signaling. Proteomic analysis identified multiple candidate proteins involved in this process; however, no single protein was sufficient to fully activate STAT3, suggesting that a combination of glycosylated proteins likely acts synergistically. In vivo, inhibition of glycolysis reduces STAT3 activation in tumors, and genetic deletion of STAT3 in subcutaneous tumor models significantly decreases tumor growth. Together, these findings uncover a novel mechanism by which glucose metabolism supports sustained STAT3 activation in CRC, highlighting a potential metabolic vulnerability for therapeutic targeting.

cancer biology↗

bioRxiv2024

Isolation and characterization of microbiota from human pancreatic tumors and small intestine

Pancreatic ductal adenocarcinoma has a unique tumor microbiome and the systemic depletion of bacteria or fungi using antibiotic/antifungal cocktails leads to a decrease in pancreatic tumor burden in mice. However, functional studies remain rare due to the limited availability of clinically relevant microbiota. Here, we describe in detail the isolation of bacteria and fungi from the small intestine and tumor of pancreatic cancer patients at the Rogel Cancer Center. We then further characterized the impact of a newly isolated Klebsiella oxytoca strain (UMKO1) on the pancreatic tumor microenvironment using bacterial genome sequencing, untargeted and targeted metabolomics, as well as an ex vivo tumor transplant system. We found that UMKO1 possesses a gene for the long form of cytidine deaminase, which can inactivate the standard PDAC chemotherapeutic agent gemcitabine. In addition, we found that UMKO1 can produce several indoles when grown in tumor-like conditions, metabolites that can lead to an immune suppressive environment and interfere with therapy outcome. To test this in detail, we assessed changes in immune populations in pancreatic tumor explants upon exposure to the supernatant of UMKO1 and other isolated bacteria grown in tumor Interstitial fluid media (TIFM). We found that while none of the bacterial supernatants changed the abundance of CD8 T cells, granzyme B positive CD8 T cells were the lowest in tumor explants exposed to UMKO1, and not other isolated Klebsiella species or the non-pathogenic laboratory strain E. coli K12. In summary, the isolated collection of bacteria and fungi from this study are a valuable toolbox to study the impact of microbiota on pancreatic cancer.

cancer biology↗

bioRxiv2022

GPR84-Mediated Signal Transduction Promotes Brown Adipocyte Function

G protein-coupled receptor 84 (GPR84), a medium-chain fatty acid receptor, may be involved in various metabolic conditions but the mechanism remains unclear. We found that GPR84 is highly expressed and functions in brown adipose tissue (BAT). GPR84 knockout mice exhibited increased adiposity and vulnerability to cold exposure after aging, along with an increased BAT lipid content and decreased BAT activation compared to wild-type control mice. In vitro, primary brown adipocytes from GPR84 knockout mice showed reduced expression of thermogenic genes and lower O2 consumption. The GPR84 agonist 6-OAU reversed these effects and restored brown adipocyte activation. In vivo and in vitro results showed that BAT defects in GPR84 knockout mice were attributed to mitochondrial dysfunction. GPR84 activation greatly affected intracellular calcium efflux, further influencing mitochondrial respiration. GPR84 activates BAT by controlling the mitochondrial calcium content and respiration, suggesting a therapeutic target for activating BAT and treating metabolic diseases. HIGHLIGHTSO_LIHigh expression of GPR84 in brown adipocytes is induced by cold stimulation. C_LIO_LIAged GPR84 knockout mice exhibit brown adipose tissue defects under cold exposure. C_LIO_LIGPR84 knockout mice show reduced mitochondrial function of brown adipocytes. C_LIO_LIGPR84 activation improves brown adipocyte functions. C_LI

physiology↗