Poplawski, P. | Search bioRxiv

bioRxiv2025

Renal cancer cell-derived amphiregulin recruits mesenchymal stromal cells, induces their glycolytic switch, and promotes tumour growth

Mesenchymal stem/stromal cells (MSCs) are multipotent cells that support wound healing. Tumours, often called as wounds that do not heal, recruit MSCs, which in turn support tumour growth. The immunomodulatory MSCs properties are facilitated under hypoxic conditions, while tumours are often hypoxic and immune-suppressed. It is unclear how MSCs wound healing actions are prevented in tumours. Here, we found that renal cancer cells secrete amphiregulin which induces MSCs recruitment and facilitates tumour growth in vivo. In MSCs, AREG triggers HIF1A degradation and transcriptional reprogramming, leading to glycolytic switch, increased migration and attenuation of immunoregulatory profile. In renal cancer cells, AREG stimulates expression of oncogenic proteins, including AKR1C3, leading to increased tumour growth and angiogenesis. To our knowledge, this is the first study showing that glycolytic switch in MSCs is induced by cancer. Our study provides insight into how renal cancer cells attenuate MSCs wound pro-healing properties to facilitate tumour growth.

cancer biology↗

bioRxiv2023

A role for LGI1 in regulating pain sensitivity.

Chronic pain represents a major unmet clinical need. Neuropathic pain, that is pain arising due to damage or disease of the somatosensory nervous system, represents a sizeable proportion of chronic pain cases, affecting around 8% of the general population. Neuronal hyperexcitability is a key driver of neuropathic pain. Leucine glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are highly effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain. Here we have studied the role of LGI1 in regulating pain using mouse models to specifically ablate LGI1 in neuron populations. LGI1 has been well studied at the level of the brain. Here we show that LGI1 is highly expressed in dorsal root ganglion (DRG) neurons and in dorsal horn neurons of the spinal cord. Using transgenic mice, we ablated LGI1, either specifically in nociceptors (LGI1fl/Nav1.8(+/-)), or in all DRG and spinal neurons (LGI1fl/Hoxb8(+/-)). On acute pain assays, mild phenotypes were observed when compared to littermate controls with limited changes in DRG neuron excitability. No differences were seen in the first phase of the formalin test, however LGI1fl/Hoxb8(+/-) mice displayed a significant increase in nocifensive behaviours in the second phase compared to littermate controls. Using the spared nerve injury model, we assessed the impact of LGI1 ablation on neuropathic pain-like behaviours. LGI1fl/Nav1.8(+/-) mice showed no differences in nerve injury induced mechanical hypersensitivity, brush-evoked allodynia or spontaneous pain behaviour compared to controls. However, LGI1fl/Hoxb8(+/-) mice showed a significant exacerbation of mechanical hypersensitivity and allodynia. These data show that LGI1 has a role in regulating pain sensitivity particularly in the context of nerve injury. We suggest this effect is likely mediated at the spinal level since no differences were observed following specific ablation of LGI1 in nociceptors. Neurons in dorsal horn of the spinal cord are important in gating nerve injury induced mechanical pain and our findings suggest that LGI1 plays an important role in this process.

neuroscience↗