Biology subjects

Stamatakis, K.

Publications and source records attributed to Stamatakis, K..

3 recordsLinked to original sources

bioRxiv2026

Improved anti-tumor vaccination activity of necroptotic cells lacking ATG16L1-dependent unconventional autophagy

Immunogenic forms of tumor cell death can induce effective anti-cancer immune responses, but the molecular mechanisms that regulate the immunogenic potential of cell suicide and how they shape anti-tumor immunity in vivo are issues that remain to be fully elucidated. Here we show that absence of unconventional autophagy mediated by the WD40 domain (WDD) of ATG16L1 increases the anti-tumor vaccinating capacity of dying cells. Necroptotic mouse carcinoma MC38 cells lacking the WDD fail to mount a concomitant unconventional autophagic response and exhibit superior vaccinating capacity against MC38 tumors inoculated afterwards. The mutant strain secretes higher levels of ATP during cell demise, whereas other Damage-Associated Molecular Patterns (DAMPs) remain unaffected. The vaccinating effect is accompanied by increased tumor immune infiltration, depends on secreted ATP and requires T cells. These results indicate that suppression of ATG16L1-mediated unconventional autophagy during tumor cell death improves anti-tumor immunity, and identify this process as a potential therapeutic target to enhance the immune contribution to control tumor development.

cancer biology↗

bioRxiv2025

A unique mechanism explaining the outstanding performance of a newly discovered doxycycline riboswitch

Synthetic riboswitches offer a versatile and protein-independent solution for conditional gene regulation. They consist of a regulatory domain and an aptamer domain that binds a specific ligand, with their performance largely depending on the ability of the aptamer to control the regulatory domain. Expanding the range of synthetic riboswitches therefore requires the discovery and characterization of new regulatory aptamers. In the present study, we identified a doxycycline-binding aptamer with outstanding regulatory properties in both yeast and human cells which are based on a unique structural dynamic upon ligand binding. Single-molecule force spectroscopy revealed that doxycycline binding strongly stabilizes an intermediate aptamer conformation offering mechanistic insights into its function. The identification of the aptamer through a combination of parallel SELEX and subsequent in vivo screening in yeast, also provided valuable insights into selection dynamics and the first proof for the effectiveness of RNA Capture-SELEX in aptamer selection. Together, the presented data deepen our understanding of regulatory aptamer selection and functionality while adding a high-performing doxycycline-responsive aptamer to the synthetic biology toolbox.

molecular biology↗

bioRxiv2018

Prostaglandin F2α-induced TGFβ-PMEPA1 pathway is a critical mediator of epithelial plasticity and ovarian carcinoma progression.

Prostaglandin (PG) F2 has been scarcely studied in cancer. We have identified a new role for PGF2 in ovarian cancer, stimulating the production of TGF{beta} and the consequent induction of PMEPA1. We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGF{beta} signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated to higher E-cadherin expression levels while {beta}-catenin nuclear translocation was inhibited. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival.\n\nSignificanceThis work identifies Prostaglandin F2 as an inducer, through NFAT, of TGF{beta} and together with this up-regulate PMEPA1, which is identified both as a drug target and as a prognostic biomarker in ovarian tumors, potentially useful in clinical practice.

cancer biology↗