Biology subjects

Sivakumar, B.

Publications and source records attributed to Sivakumar, B..

3 recordsLinked to original sources

bioRxiv2025

Macrophage migration inhibitory factor is a potential therapeutic target for cisplatin induced peripheral neuropathy in breast cancer

BackgroundCisplatin (CP) is an effective chemotherapy drug for several cancers. However, the use of CP is associated with peripheral neuropathy, a painful nerve disorder. Unfortunately, no therapies are available for CP-induced peripheral neuropathy (CisIPN). This study explored the role of a cytokine, the macrophage migration inhibitory factor (MIF), as a potential therapeutic target for CisIPN. MethodsThe role of neuroinflammation and MIF in CisIPN was evaluated in mice models of CisIPN, with and without breast cancer, after treatment with the anti-inflammatory drug Dexamethasone (Dex). Circulating MIF levels in animals were examined using ELISA. Pharmacological inhibition of MIF was achieved using the small molecule inhibitors, CPSI-1306 and ISO-1. Mechanical and thermal sensitivities of animals were assessed using von frey filament and cold acetone assays. Macrophage infiltration in peripheral nerve tissues was examined using CD68 and Iba-1 staining. ResultsOur results showed that Dex suppressed mechanical hyperalgesia in CisIPN animals, which was accompanied by downregulation of MIF. We also found that circulating MIF levels were increased in CisIPN animals. Furthermore, direct inhibition of MIF using CPSI-1306 and ISO-1 led to suppression of mechanical hyperalgesia, without compromising the anti-tumor efficacy of CP, in CisIPN animals. We did not find any significant change in macrophage infiltration in the peripheral nerve tissues of CisIPN animals. Immunostaining results indicated that sensory neurons in the DRGs and Schwann Cells in the sciatic nerves are potential sources for increased MIF in CisIPN. InterpretationOverall, our results strongly suggest that MIF is a promising therapeutic target for CisIPN.

neuroscience↗

bioRxiv2025

Molecular and cellular features of nerve-invaded cancer cells using a newly characterized experimental model

Perineural invasion (PNI) is the invasion of cancer cells into nerves. Although PNI is a risk factor for cancer recurrence and metastasis, the lack of in vitro experimental models representing natural PNI challenges basic studies and therapeutic screening. In this work, we fully characterized a dorsal root ganglia (DRG)-nerve explant model for PNI and demonstrated the characteristic cellular and molecular features of cancer cells undergoing natural PNI. Briefly, thoracic and lumbar DRGs intactly connected to nerves were co-cultured with breast and prostate cancer cells in a 3D matrix for two weeks. Time-dependent brightfield and fluorescence imaging captured the complex interactions of cancer cells, neurons, axons, and Schwann cells within nerves in the DRG-nerve explant, demonstrating the natural invasion of cancer cells. Fundamental investigations showed that the autonomic neurotransmitters norepinephrine and acetylcholine significantly promote PNI. We also demonstrated increased survival of PNI cells against the cytotoxic drug cisplatin. Additionally, we characterized the proteomics profile of PNI cells for future theranostics applications and validated the results using patient breast tumor samples. Overall, this work characterized and established a clinically relevant model for PNI and revealed the cellular crosstalk of PNI cells within nerves. The established model is suitable for fundamental studies and therapeutic screening pertaining to PNI.

cancer biology↗

bioRxiv2025

Schwann cells modified to secrete MANF is a potential cellular therapy for peripheral nerve regeneration

Despite several decades of research, an effective therapy for peripheral nerve regeneration is still lacking. The lack of knowledge of molecular candidates that equally promote axon regeneration and glial cell dynamics essential for regeneration poses challenges in developing effective therapies. Improper optimization of potential therapies leading to failures in ensuring their local availability in nerves also poses additional challenges. Here, we showed that the neurotrophic factor, the mesencephalic astrocyte-derived neurotrophic factor (MANF), equally promotes axon regeneration and glial cell dynamics favorable for nerve regeneration. We showed that while endogenous expression of MANF is primarily restricted to non-peptidergic sensory neurons in adult rats, exogenous MANF promotes the growth of all subtypes of adult rat sensory neurons. We also demonstrated that exogenous MANF promotes the proliferation and migration of adult rat primary Schwann Cells (SCs). Further, we found that local and repeated administration of exogenous MANF to injured mouse nerve promote axon regeneration. Finally, we devised a therapeutic approach by programming nerve resident SCs to locally and continuously deliver MANF to injured rat nerves and showed that this approach improved nerve regeneration indices. Overall, this work developed a therapeutic approach by harnessing the power of SCs as a local delivery system of MANF for improving nerve regeneration.

neuroscience↗