Biology subjects

Ponnusamy, V.

Publications and source records attributed to Ponnusamy, V..

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↗

bioRxiv2025

Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cells

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. CRC tumors exhibit aberrant iron accumulation, which supports tumor cell proliferation through multiple metabolic pathways. However, the oncogenic benefits of elevated iron must be counterbalanced by its potential to catalyze oxidative damage via reactive oxygen species generated from labile, redox-active iron. Ferroptosis is a regulated, non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. This process is tightly controlled by the selenoenzyme glutathione peroxidase 4 (GPX4), which reduces lipid peroxides and can be pharmacologically inhibited by agents such as RSL3 and JKE1674. A key source of redox-active iron is the labile iron pool (LIP), yet its role in regulating ferroptosis remains incompletely defined. To examine this, we supplemented CRC cells with exogenous iron following pharmacologic induction of ferroptosis. Iron supplementation significantly reduced cell viability, suggesting that expansion of the LIP potentiates ferroptotic cell death. However, whether ferroptosis is accompanied by dynamic changes in the LIP, and if such changes are mechanistically required for its potentiation, were unknown. To further characterize this response, we profiled the expression of iron regulatory genes under ferroptotic conditions and observed no change in transcriptional response in iron homeostasis genes. Using a reactivity-based probe of labile iron, we found that the LIP did not measurably increase during ferroptosis induction with GPX4 inhibition or inhibition of the SLC7A11 cysteine/glutamate antiporter. These findings suggest that the LIP does not expand upon pharmacological initiated ferroptosis, despite the potentiating effect of exogenous iron supplementation.

cancer biology↗

bioRxiv2024

A spatially-resolved blueprint of the developing human lung reveals a basal cell population regulated by a WNT-driven niche

Organs are composed of diverse cell types that change across space and time during development. To interrogate this diversity, we micro-dissected developing human lungs along the proximal-distal axis during the late pseudoglandular stage and generated an integrated analysis of single-nucleus sequencing and spatial transcriptomics, creating a cellularly-resolved atlas of the lung. These rich datasets revealed positional niches and cellular heterogeneity along the proximal-distal axis, including the identification of a unique population of TP63+ basal cells, the primary stem cell of the airway, marked by expression of LGR5 and LGR6. Analysis of the LGR5+ basal cell niche and functional experiments with primary organoid models suggest a tonic level of WNT pathway activity in LGR5+ basal cells that is potentiated by mesenchyme-derived R-SPONDIN. We found that basal cell self-renewal is enhanced by WNT activity, suggesting that the WNT pathway plays a previously unappreciated but critical role in airway stem cell maintenance during human development. These results enhance our fundamental understanding of the positional and cellular heterogeneity in the developing human lungs and begin to reveal unique niches that maintain homeostasis throughout the lung.

developmental biology↗