Biology subjects

Michelakis, E. D.

Publications and source records attributed to Michelakis, E. D..

4 recordsLinked to original sources

bioRxiv2026

Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence

Metastatic prostate cancer remains a lethal disease, with most treatments focusing on the androgen receptor (AR) axis. We identified the zinc finger protein 281 (ZNF281) as a previously unrecognized driver of metastatic prostate cancer that promotes both AR-related transcriptional output and distinct AR-independent tumor-promoting pathways. It increases AR expression and acts as a coactivator to promote AR transcriptional activity. Independent of AR, ZNF281 promotes prostate cancer by upregulating SMURF1 to sustain tumor growth and by promoting SNAIL-mediated metastasis. We developed an orally bioavailable, ZNF281 Interfering Molecule (Oral ZIM) that disrupts its DNA binding and AR protein interaction. Knockout of ZNF281 as well as treatment with oral ZIM potently inhibited prostate cancer growth and metastasis in orthotopic xenograft models of castration-sensitive and castration-resistant prostate cancers (without detectable systemic toxicity), and ZIM outperformed enzalutamide treatment in patient-derived prostate cancer organoids.

cancer biology↗

bioRxiv2026

An inducer of snail hibernation causes quiescence and hibernation-like cardioprotection, through metabolic rewiring and autophagy, in mice hearts

Cells of hibernators achieve dormancy, resembling cellular quiescence, through molecular rewiring, metabolic remodelling and autophagy, resisting ischemic and ischemia-reperfusion (IR) injury, while non-hibernators are vulnerable to both. We discovered a circulating dormancy-inducing factor in hibernating snails, synthesized it chemically and because it activates PHLPP1 (a phosphatase regulating the mTOR mediators p-AKT and p-S6K1), named it SNail Activator of PHLPP1 (SNAP). During IR, plasma membrane PHLPP1 and p-AKT translocate to the cytoplasm and mitochondria. SNAP dephosphorylates mitochondrial p-AKT, p-S6K1 and induces dormancy in snails and quiescence (autophagy, reversible cell-cycle exit, proteostasis, apoptosis-resistance) in ischemic mouse fibroblasts. In IR models of cardiomyocytes and perfused hearts, SNAP is cardioprotective by preserving Pyruvate Dehydrogenase (PDH) activity, preventing mitochondrial depolarization, apoptosis and ROS-induced ER stress. SNAPs cardioprotective and mitochondrial effects are absent in hearts with a cardiomyocyte-specific PDH knockout. SNAP reveals fundamental mechanisms of quiescence under stress; while its cardioprotection may be beneficial in the IR injury of normal hearts offered for transplantation, a major challenge in transplant medicine.

cell biology↗

bioRxiv2025

A critical contribution of cardiac myofibroblasts in right ventricular failure and the role of UCP2 SNPs in the predisposition to RV decompensation in pulmonary arterial hypertension

The mechanism of transition from compensated (cRV) to decompensated right ventricle (dRV) in pulmonary arterial hypertension (PAH) is unknown. We explored the role of RV cardiac myofibroblasts (cMFB) on this transition utilizing a rat model and 3 cohorts of 81 patients which included clinical data, RV tissues and blood. We hypothesized that the loss of UCP2, critical for mitochondrial calcium (mCa++) regulation and cardiac fibroblasts (cFB) differentiation, is associated with dRV in rats and humans; and that a loss-of-function UCP2 SNP (rs659366) may predict dRV in human PAH. We separated rat cRV from dRV based on catheterization and echocardiographic criteria and found a significant increase in cMFB in dRV. In isolated hearts, RV contractility was lower in dRV but not in isolated cardiomyocyte (CM), pointing to a non-CM cause. Mitochondrial respiration was lower in dRV cMFB than in control and cRV cFB. mCa++ was progressively decreased from normal to cRV to dRV c(M)FB, and the same was true for c(M)FB (but not CM) UCP2 levels. Human PAH, but not secondary pulmonary hypertension, dRVs had more cMFB and less UCP2 than control and cRVs. Decreased UCP2 (protein and mRNA) levels and the presence of heterozygous/homozygous UCP2 SNP were associated with worse RV performance (TAPSE, cardiac index), even among patients with similar mean pulmonary arterial pressure. Our data point to a change of cell identity (cFB to cMFB) in the RV as a driver of RV decompensation. UCP2 SNPs are promising biomarkers for early cRV transition to dRV in PAH.

molecular biology↗

bioRxiv2025

Hyperacute Response Proteins (HARPs) synthesized on γ-tubulin-FTO-MARK4 translation microdomains upon exposure to stress, regulate stressresponse in cancer.

Compared to normal, cancer cells are particularly resistant to stress, and their immediate response to stress is critical for their subsequent multilayered adaptation programs which pose a major clinical challenge. With unbiased proteomics and transcriptomics analysis, we identified a list of HARPs synthesized from pre-existing mRNAs within 20 min of diverse stresses in A549 cancer cells, despite the known suppressed global translation in stress. HARP mRNAs were translated on microtubule-associated translation microdomains (MATMs) located on {gamma}-tubulin, that host FTO and specialized cytoskeletal ribosomes, structurally and functionally distinct from ER and cytosolic ribosomes. FTO exited the nucleus immediately after stress and was activated by the microtubule-associated stress kinase MARK4 via T6 phosphorylation. Activated FTO demethylated a translation-inhibiting mRNA methylation (m6A) signature, facilitating compartmentalized HARP translation on MATMs, while non-HARP mRNA remained inhibited. FTO or MARK4 inhibition suppressed HARP synthesis and increased apoptosis post various stresses, including chemotherapy. These data were confirmed in 4 additional cancer cell lines and normal fibroblasts. Using the Protein Atlas database, we found that high levels of our identified HARPs had on average a 35% decrease on patient 5-year survival in prevalent and resistant cancers (breast, lung, liver, pancreas). {gamma}-tubulin, FTO and MARK4 are therapeutic targets for many cancers, through their ability to comprehensively promote HARPs translation, a potential Achilles heel for cancers resistance to physiologic or therapeutic stress, offering a new window in stress biology.

cancer biology↗