Targeting the gp130/STAT3 Axis Attenuates Tumor Microenvironment Mediated Chemoresistance in Group 3 Medulloblastoma
Lakshana Sreenivasan1,2, Ling Vicky Li1,3, Pascal Leclair1,4
1Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada.
Abstract:
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four molecular subgroups, Group 3 MB is the most aggressive and has the worst prognosis. To understand the origins of chemoresistance involving IL-6/STAT3 signaling, we used in vitro co-culture systems to investigate the contribution of microglia as a brain tumor microenvironment cellular source of paracrine cytokines that promotes acquired drug resistance in Group 3 MB. MB cells subjected to co-culture with microglia exhibited increased expression of phosphorylated JAK1 and STAT3, which was correlated with enhanced resistance to vincristine. We found that both microglia and MB cells co-cultured with microglia secreted significant quantities of IL-6, indicating that IL-6 is a paracrine and autocrine cytokine able to initiate and sustain STAT3 activity in MB cells. Surprisingly, IL-6R-/- MB cells, which cannot respond to exogenous IL-6 stimuli, were responsive to microglia co-culture induced activation of STAT3 and chemoresistance. Subsequently, we found that MB cells conditioned in vitro with the IL-6 family cytokines, IL-6, OSM, LIF, or IL-11, exhibited enhanced JAK1/STAT3 activity and chemoresistance. Intriguingly, MB cells conditioned with any one of the IL-6 family cytokine secreted multiple IL-6 family cytokines, implicating a feedback network involving multiple cytokines. The IL-6 family cytokine receptors share a common signal transducing β-subunit, gp130, which may be targeted to mitigate tumor chemoresistance. We showed that microglia co-culture failed to induce chemoresistance of gp130-/- MB cells, and that combination treatment using gp130 inhibitors, or with the JAK inhibitor ruxolitinib, effectively overcame the observed resistance to vincristine in gp130 expressing MB cells. Our in vitro studies highlight the gp130/JAK/STAT pathway as a therapeutic target in combating acquired treatment resistance in Group 3 MB.
Insights
Microglia promote chemoresistance in Group 3 medulloblastoma (MB) by activating the IL-6/STAT3 pathway. Targeting the gp130/JAK/STAT pathway, particularly with gp130 or JAK inhibitors, can overcome this resistance in pediatric brain tumors.
Area of Science:
- * Oncology
- * Neuroscience
- * Immunology
Background:
- * Medulloblastoma (MB) is the most common malignant pediatric brain tumor.
- * Group 3 MB is the most aggressive subgroup with the poorest prognosis.
- * Understanding chemoresistance mechanisms is crucial for improving treatment outcomes.
Purpose of the Study:
- * To investigate the role of microglia in promoting chemoresistance in Group 3 MB.
- * To elucidate the involvement of the IL-6/STAT3 signaling pathway in acquired drug resistance.
- * To identify potential therapeutic targets for overcoming chemoresistance in Group 3 MB.
Main Methods:
- * In vitro co-culture systems of Group 3 MB cells and microglia.
- * Analysis of phosphorylated JAK1 and STAT3 expression.
- * Measurement of IL-6 secretion.
- * Use of cytokine receptor knockout (IL-6R-/-, gp130-/-) MB cells.
- * In vitro conditioning of MB cells with IL-6 family cytokines.
- * Assessment of chemoresistance to vincristine.
- * Evaluation of gp130 inhibitors and JAK inhibitor ruxolitinib.
Main Results:
- * Microglia co-culture increased phosphorylated JAK1/STAT3 and vincristine resistance in MB cells.
- * Both microglia and co-cultured MB cells secreted IL-6, suggesting paracrine and autocrine signaling.
- * IL-6 receptor deficient MB cells still showed STAT3 activation and chemoresistance upon microglia co-culture.
- * Conditioning with IL-6 family cytokines (IL-6, OSM, LIF, IL-11) enhanced JAK1/STAT3 activity and chemoresistance.
- * A feedback network involving multiple IL-6 family cytokines was implicated.
- * gp130 deficient MB cells did not develop chemoresistance upon microglia co-culture.
- * gp130 inhibitors or ruxolitinib overcame vincristine resistance in gp130 expressing MB cells.
Conclusions:
- * Microglia contribute to acquired chemoresistance in Group 3 MB via the IL-6/STAT3 pathway.
- * The gp130/JAK/STAT pathway is a critical mediator of this resistance.
- * Targeting gp130 or JAK signaling presents a promising therapeutic strategy for Group 3 MB.
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