Biology subjects

Kheirabadi, S.

Publications and source records attributed to Kheirabadi, S..

3 recordsLinked to original sources

bioRxiv2026

Convergent Roles of Growth Differentiation Factor-15 (GDF-15) in Mechanotransduction, Vascular Disorganization, and Immune Suppression in Melanoma

Melanoma, particularly in its advanced forms, remains one of the most lethal skin cancers, with limited effective treatments for both common cutaneous subtypes and rarer variants such as acral melanoma. The effects of the extracellular matrix (ECM) and other cancer-cell extrinsic processes on melanoma development remain underexplored. This study identifies Growth Differentiation Factor-15 (GDF-15) as a novel mechanosensing-regulated driver of melanoma pathogenesis across melanoma types. GDF-15 is shown here to be mechanically induced by ECM rigidity and compressive forces occurring during metastatic progression, leading to significantly elevated levels in both cutaneous and acral melanoma cells. In this study, ECM rigidity was recapitulated using cell-adhesive gelatin methacryloyl (GelMA) hydrogel microparticles (microgels) with tunable stiffness, providing a biomimetic platform to investigate how mechanical cues in the tumor microenvironment regulate GDF-15 expression in melanoma. A previously unrecognized synergy between GDF-15 and inflammatory factors commonly present in tumors was identified and found to promote a disorganized, hyperpermeable vasculature, thereby facilitating tumor nutrient access and impeding effective immune cell infiltration. GDF-15 knockdown reduced the intratumoral hemorrhage phenotype, indicating a causal role. GDF-15 also functions by directly suppressing natural killer (NK) cell-mediated cytotoxicity, revealing a second cooperating mechanism of immune evasion. These effects position GDF-15 as a key node linking mechanical stress, co-operation with inflammatory factors, abnormal vascular development, and immune dysfunction, thereby converging on a pathways and processes not previously described in melanomas. TEASERUncovering GDF-15 as a central mediator at the intersection of mechanical rigidity and external force, disorganized vascular hemorrhagic remodeling, co-operation with inflammatory factors, and immune evasion, revealing a previously unrecognized therapeutic vulnerability across both common and rare melanoma subtypes

cancer biology↗

bioRxiv2023

Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer

Metastasis is a principal cause of death in cancer patients, which remains an unresolved fundamental and clinical problem. Conventionally, metastatic dissemination is linked to the actomyosin-driven cell locomotion. However, locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Here, we identify a complementary mechanism of metastatic locomotion powered by the dynein-generated forces. These forces that arise within a non-stretchable microtubule network drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers. We also show that dynein-powered locomotion becomes indispensable during invasive 3D migration within a tissue-like luminal network between spatially confining hydrogel microspheres. Our results indicate that the complementary contractile system of dynein motors and microtubules is always necessary and in certain instances completely sufficient for dissemination of metastatic breast cancer cells. These findings advance fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis.

cell biology↗

bioRxiv2022

Iron Inhibits Glioblastoma Cell Migration and Polarization

Glioblastoma is one of the deadliest malignancies facing modern oncology today. The ability of glioblastoma cells to diffusely spread into neighboring healthy brain makes complete surgical resection nearly impossible and contributes to the recurrent disease faced by most patients. Although research into the impact of iron on glioblastoma has addressed proliferation, there has been little investigation into how cellular iron impacts the ability of glioblastoma cells to migrate - a key question especially in the context of the diffuse spread observed in these tumors. Herein, we show that increasing cellular iron content results in decreased migratory capacity of human glioblastoma cells. The decrease in migratory capacity was accompanied by a decrease in cellular polarization in the direction of movement. Expression of CDC42, a Rho GTPase that is essential for both cellular migration and establishment of polarity in the direction of cell movement, was reduced upon iron treatment. Bioinformatic analysis of CDC42 mRNA revealed a potential iron-responsive element that may contribute to the regulation of CDC42 by iron. We then analyzed a single-cell RNA-seq dataset of human glioblastoma samples and found that cells at the tumor periphery had a gene signature that is consistent with having lower levels of cellular iron. Altogether, our results suggest that cellular iron content is impacting glioblastoma cell migratory capacity and that cells with higher iron levels exhibit reduced motility.

cancer biology↗