Mohammad-Reza Shokri

Primary cilia are microtubule-based sensory organelles that coordinate key oncogenic signaling pathways, including Hedgehog, Wnt, PDGF, and TGF-β. Mitochondria, traditionally viewed as bioenergetic hubs, also regulate redox balance, calcium homeostasis, apoptosis, and metabolic plasticity. Emerging evidence demonstrates that these organelles are functionally coupled, forming a bidirectional ciliary-mitochondrial axis that influences cancer progression and metastasis. Disruption of ciliogenesis, often through IFT88 or KIF3A loss, impairs mitochondrial oxidative phosphorylation and promotes a glycolytic, biosynthetic phenotype. Conversely, mitochondrial dysfunction, excessive reactive oxygen species (ROS), and altered dynamics feedback to regulate ciliary assembly and signaling. Key mechanistic nodes include calcium flux, AMPK-ULK1 signaling, ROS-mediated communication, and the recently identified NDUFAF2-ARMC9 bridge linking mitochondrial metabolism to ciliogenesis. This crosstalk converges on pathways that drive epithelial-to-mesenchymal transition, cancer stemness, migration, invasion, and therapeutic resistance. In the tumor microenvironment, hypoxia, nutrient deprivation, immune signaling, and extracellular vesicles further modulate this axis, contributing to metabolic heterogeneity and metastatic dissemination. Importantly, the relationship between cilia and cancer is context-dependent: cilia can be tumor-suppressive in some malignancies yet support oncogenic signaling in others. These insights suggest that targeting ciliary function, mitochondrial metabolism, or their intersection may offer novel therapeutic opportunities. This review synthesizes current evidence on ciliary-mitochondrial crosstalk, highlights unresolved mechanistic questions, and proposes an integrated framework for understanding how this organellar axis shapes cancer evolution and treatment response. We propose that integrated ciliary-mitochondrial signatures represent highly promising novel cancer biomarkers capable of predicting tumor plasticity, metastatic risk, and therapeutic response beyond conventional single-organelle or genomic markers.

Physiological cardiac hypertrophy is a compensatory remodeling of the heart in response to stimuli such as exercise training or pregnancy that is reversible and well-tolerated. We previously described how the activating transcription factor 6 (ATF6) proteins, ATF6α and ATF6β, were required for pathological hypertrophy in response to hemodynamic stress. Here, we examine the functional roles of both ATF6 proteins in the context of exercise-induced physiological hypertrophy. After 20 days of swim training, we found differential roles: whole body gene-deleted mice lacking ATF6α had an attenuated hypertrophic response compared to wild-type mice but those lacking ATF6β did not. Additionally, mice lacking ATF6α displayed ventricular dilation and reduced fractional shortening after swimming. While we observed no differences in the expression of downstream UPR signaling between the exercise groups, mice lacking ATF6α showed enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). Thus, in response to swim training, loss of ATF6β did not hinder the development of physiological hypertrophy, but loss of ATF6α resulted in significantly reduced cardiac fractional shortening.

Viral aseptic meningitis is a neuroinflammatory condition that occurs when viruses gain access to the central nervous system (CNS) and induce inflammation. The blood–brain barrier (BBB) is comprised of brain endothelial cells (BECs) that stringently regulate the passage of molecules, toxins, and pathogens from the circulation into the CNS. Through their unique properties, such as complex tight junctions, reduced rates of endocytosis, expression of efflux transporters, and restricted expression of leukocyte adhesion molecules, the BBB is often able to limit pathogen entry into the brain; however, certain neurotropic pathogens, such as coxsackievirus B3 (CVB3) are able to infect the CNS. We have previously demonstrated that CVB3 can infect and disrupt induced pluripotent stem cell-derived brain-like endothelial cells (iBECs), but the host response to this infection remains unknown. Here, we investigate global host transcriptional changes during CVB3 infection of iBECs using RNA sequencing. We validated our data set by exploring pathways altered by CVB3 using quantitative real-time PCR (qPCR) and enzyme-linked immunosorbent assay of upregulated cytokines and interferon signaling molecules. IMPORTANCE: Coxsackievirus B3 (CVB3) is a leading cause of viral aseptic meningitis that can produce severe disease in susceptible individuals. To gain access to the central nervous system, CVB3 must cross central nervous system barriers, such as the blood–brain barrier. Previously, we have shown that CVB3 infects a human stem cell-derived brain-like endothelial cell model. Here, we report the global transcriptome of stem cell-derived brain-like endothelial cells to CVB3 infection and provide proof-of-concept validation of the dataset using molecular biology techniques. These data could inform novel mechanisms of CVB3-mediated blood–brain barrier dysfunction.

Melanoma has increased in incidence worldwide prompting investigators to search for new biomarkers for targeted immunotherapy of this disease. Placenta specific 1 (PLAC1) is a new member of cancer-...

Although natural killer (NK) cells play a crucial role in the maintenance of a successful pregnancy, their cytotoxic activity should be tightly controlled. We hypothesized that endometrial mesenchymal stromal/stem cells (eMSCs) could potentially attenuate the functional features of NK cells. Herein, we assessed immunomodulatory effects of menstrual blood-derived stromal/stem cells (MenSCs), as a surrogate for eMSCs, on NK cells function. Our results showed that MenSCs induced proliferation of NK cells. However, IFN-γ/IL-1β pretreated MenSCs significantly inhibited NK cell proliferation. Of 41 growth factors tested, MenSCs produced lower levels of insulin-like growth factor binding proteins (IGFBPs) 1–4, VEGF-A, β-NGF, and M-CSF compared to bone marrow-derived mesenchymal stem cells (BMSCs). MenSCs displayed high activity of IDO upon IFN-γ treatment. The antiproliferative potential of IFN-γ/IL-1β-pretreated MenSCs was mediated through IL-6 and TGF-β. MenSCs impaired the cytotoxic activity of NK cells on K562 cells, consistent with the lower expression of perforin, granzymes A, and B. We also observed that in vitro decidualization of MenSCs in the presence of IFN-γ reduced the inhibitory effect of MenSCs on NK cell cytotoxicity against K562 target cells. Additionally, MenSCs were found to be prone to NK cell-mediated lysis in an MHC-independent manner. Our findings imply that dysregulation of NK cells in such pregnancy-related disorders as miscarriage may stem from dysfunctioning of eMSCs.

This is the first study demonstrating the efficacy of menstrual blood-derived stem cell (MenSC) transplantation via decellularized human amniotic membrane (DAM), for the promotion of skin excisional wound repair. The DAM was seeded with MenSCs at the density of 3 × 10⁴ cells/cm² and implanted onto a rat’s 1.50 × 1.50 cm² full-thickness excisional wound defect. The results of wound closure and histopathological examinations demonstrated that the MenSC-seeded DAM could significantly improve the wound healing compared with DAM-treatment. All in all, our data indicated that the MenSCs can be a potential source for cell-based therapies to regenerate skin injuries.