Biology subjects

Roweth, H. G.

Publications and source records attributed to Roweth, H. G..

3 recordsLinked to original sources

bioRxiv2025

Platelet-Mediated Suppression of T Cell Function Drives Immune Evasion in Triple Negative Breast Cancer through the P-Selectin / PSGL-1 Pathway

Immune checkpoint inhibitors (ICIs) have demonstrated clinical promise in triple-negative breast cancer (TNBC), yet their effectiveness is often limited by acquired resistance and immune refractoriness. This underscores the urgent need to improve strategies that restore or enhance anti-tumor immunity. Platelets--long recognized for their role in hemostasis--have emerged as key immunomodulators in cancer by interacting with circulating tumor cells, shielding them from sheer stress and immune clearance while actively promoting immune evasion. Here, we uncover a previously unrecognized immunoregulatory pathway whereby platelet-derived P-selectin engages P-selectin glycoprotein ligand-1 (PSGL-1) on T cells, triggering immunosuppressive signaling and promoting T-cell exhaustion. This interaction, identified using in vitro co-culture systems and validated in in vivo mouse models of TNBC, reveals a targetable form of platelet-mediated immune suppression that contributes to ICI resistance. PSGL-1, traditionally known for mediating leukocyte trafficking, functions here as an immune checkpoint receptor, further underscoring the therapeutic relevance of this axis. Together, our findings highlight the P-selectin-PSGL-1 interaction as a novel and targetable mechanism of immune evasion and provide preclinical evidence that its disruption may enhance ICI responsiveness and improve outcomes in TNBC. Key PointsO_LITumor-associated platelets (TAPs) exhaust T-cells through P-selectin/P-selectin glycoprotein ligand-1 binding C_LIO_LIPharmaceutical blockade of P-selectin using Crizanlizumab, prevents exhaustion and allows T-cell function C_LI

cancer biology↗

bioRxiv2024

Inhibition of RhoA-mediated secretory autophagy in megakaryocytes mitigates myelofibrosis in mice

Megakaryocytes (MKs) are large, polyploid cells that contribute to bone marrow homeostasis through the secretion of cytokines such as transforming growth factor {beta}1 (TGF{beta}1). During neoplastic transformation, immature MKs accumulate in the bone marrow where they induce fibrotic remodeling ultimately resulting in myelofibrosis. Current treatment strategies aim to prevent MK hyperproliferation, however, little is understood about the potential of targeting dysregulated cytokine secretion from neoplastic MKs as a novel therapeutic avenue. Unconventional secretion of TGF{beta}1 as well as interleukin 1{beta} (IL1{beta}) via secretory autophagy occurs in cells other than MKs, which prompted us to investigate whether similar mechanisms are utilized by MKs. Here, we identified that TGF{beta}1 strongly co-localized with the autophagy marker light chain 3B in native MKs. Disrupting secretory autophagy by inhibiting the small GTPase RhoA or its downstream effector Rho kinase (ROCK) markedly reduced TGF{beta}1 and IL1{beta} secretion in vitro. In vivo, conditional deletion of the essential autophagy gene Atg5 from the hematopoietic system limited megakaryocytosis and aberrant cytokine secretion in an MPLW515L-driven transplant model. Similarly, mice with a selective deletion of Rhoa from the MK and platelet lineage were protected from progressive fibrosis. Finally, disease hallmarks in MPLW515L-transplanted mice were attenuated upon treatment with the autophagy inhibitor hydroxychloroquine or the ROCK inhibitor Y27632, either as monotherapy or in combination with the JAK2 inhibitor ruxolitinib. Overall, our data indicate that aberrant cytokine secretion is dependent on secretory autophagy downstream of RhoA, targeting of which represents a novel therapeutic avenue in the treatment of myelofibrosis. One Sentence SummaryTGF{beta}1 is released from megakaryocytes via RhoA-mediated secretory autophagy, and targeting this process can alleviate fibrosis progression in a preclinical mouse model of myelofibrosis.

cell biology↗

bioRxiv2020

Predicting the Health Impact of Dietary Polyphenols Using a Network Medicine Framework

Polyphenols, natural products present in plant-based foods, play a protective role against several complex diseases through their antioxidant activity and by diverse molecular mechanisms. Here we developed a network medicine framework to uncover the mechanistic roles of polyphenols on health by considering the molecular interactions between polyphenol protein targets and proteins associated with diseases. We find that the protein targets of polyphenols cluster in specific neighborhoods of the human interactome, whose network proximity to disease proteins is predictive of the molecules known therapeutic effects. The methodology recovers known associations, such as the effect of epigallocatechin 3-O-gallate on type 2 diabetes, and predicts that rosmarinic acid (RA) has a direct impact on platelet function, representing a novel mechanism through which it could affect cardiovascular health. We experimentally confirm that RA inhibits platelet aggregation and alpha granule secretion through inhibition of protein tyrosine phosphorylation, offering direct support for the predicted molecular mechanism. Our framework represents a starting point for mechanistic interpretation of the health effects underlying food-related compounds, allowing us to integrate into a predictive framework knowledge on food metabolism, bioavailability, and drug interaction.

bioinformatics↗