Article highlights & insights
- TIAM1 is upregulated in neuroendocrine compared to non-neuroendocrine SCLC cells
- TIAM1-RAC1 inhibition decreases SCLC cell viability by increasing apoptosis
- TIAM1 interacts with and maintains Nur77 nuclear localisation
- TIAM1-RAC1 inhibition causes Nur77 relocalisation and pro-apoptotic BCL2 conversion
Small-cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analyzing expression data from SCLC tumors, patient-derived models, and established cell lines, we show that the expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduces viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion is dependent upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promotes Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding fails to suppress apoptosis triggered by TIAM1 depletion. In conclusion, TIAM1-RAC1 signaling promotes SCLC cell survival via Nur77 nuclear sequestration.
- TIAM1 is upregulated in neuroendocrine compared to non-neuroendocrine SCLC cells
- TIAM1-RAC1 inhibition decreases SCLC cell viability by increasing apoptosis
- TIAM1 interacts with and maintains Nur77 nuclear localisation
- TIAM1-RAC1 inhibition causes Nur77 relocalisation and pro-apoptotic BCL2 conversion
Small-cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analyzing expression data from SCLC tumors, patient-derived models, and established cell lines, we show that the expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduces viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion is dependent upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promotes Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding fails to suppress apoptosis triggered by TIAM1 depletion. In conclusion, TIAM1-RAC1 signaling promotes SCLC cell survival via Nur77 nuclear sequestration.
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Amaya Virós
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“We are so pleased to have received the funding to enable us to test our hypothesis in the lab. If we can create a new medicine that can precisely target a specific type of cell within the tumour, and restore anti-cancer immune responses, this will be a game-changer for oesophageal cancer patients “
Sara Valpione
Former Institute Clinical Fellow and now Clinician in Residence within the CRUK National Biomarker Centre
“My charity bake sales – known as “David’s Great British Bake Off” – are always a hit, home baked products taste so much better than shop bought and are greatly appreciated by staff!”
David Jenkins
Purchasing Officer
“We’ve seen some remarkable responses, with an improvement for some patients within days. This is an early phase trial so there’s a lot more work to do. But the data we have so far is very encouraging and could help many thousands of people in the future”
Tim Somervaille
Senior Group Leader
“It is a pleasure to introduce my team who work to deliver our research goals. We work in a friendly and collaborative environment, supporting each other’s projects. “
Amaya Virós
CRUK Advanced Clinician Scientist Fellow