IQGAP3 bridges matrix stiffness with cancer stem cell maintenance and radioresistance by stabilizing SOX2
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ABSTRACT:
PROVIDER: PRJNA1233241 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32610000_1.fastq.gz | Fastqsanger.gz | |||
| SRR32610000_2.fastq.gz | Fastqsanger.gz | |||
| SRR32609997_1.fastq.gz | Fastqsanger.gz | |||
| SRR32609997_2.fastq.gz | Fastqsanger.gz | |||
| SRR32609998_1.fastq.gz | Fastqsanger.gz |
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Project description:Drivers of therapeutic resistance in cancer include evolution of tumor cell heterogeneity and the tumor microenvironment (TME). Here, we found that increased matrix stiffness promotes radioresistance in glioblastoma (GBM) and maintains the tumor cell hierarchy. Differential gene expression revealed that stiff matrices induced expression of IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) specifically in GBM stem cells (GSCs). IQGAP3 promoted GSC self-renewal and survival upon radiation treatment through binding and stabilization of the core stem cell transcription factor, SOX2. Targeting IQGAP3 reduced SOX2 protein levels in vitro and in vivo, increasing GSC radiosensitivity and inhibiting tumor growth. Structure-function drug screening of FDA-approved agents blocking IQGAP3 binding to SOX2 identified Trimetrexate as a brain penetrant pharmacologic disruptor of IQGAP3 function in radioresistance, sensitizing GSCs to radiotherapy. Our results identify molecular underpinnings for biomechanical promotion of cancer stem cell maintenance and therapeutic resistance, informing a therapeutic strategy to augment efficacy of radiotherapy.
2025-03-08 | GSE291362 | GEO
Project description:Drivers of therapeutic resistance in cancer include evolution of tumor cell heterogeneity and the tumor microenvironment (TME). Here, we found that increased matrix stiffness promotes radioresistance in glioblastoma (GBM) and maintains the tumor cell hierarchy. Differential gene expression revealed that stiff matrices induced expression of IQGAP3 (IQ Motif Containing GTPase Activating Protein 3) specifically in GBM stem cells (GSCs). IQGAP3 promoted GSC self-renewal and survival upon radiation treatment through binding and stabilization of the core stem cell transcription factor, SOX2. Targeting IQGAP3 reduced SOX2 protein levels in vitro and in vivo, increasing GSC radiosensitivity and inhibiting tumor growth. Structure-function drug screening of FDA-approved agents blocking IQGAP3 binding to SOX2 identified Trimetrexate as a brain penetrant pharmacologic disruptor of IQGAP3 function in radioresistance, sensitizing GSCs to radiotherapy. Our results identify molecular underpinnings for biomechanical promotion of cancer stem cell maintenance and therapeutic resistance, informing a therapeutic strategy to augment efficacy of radiotherapy.
2025-03-14 | GSE291583 | GEO
Project description:IQGAP3 bridges matrix stiffness with cancer stem cell maintenance and radioresistance by stabilizing SOX2 II
| PRJNA1234192 | ENA
Project description:IQ motif containing GTPase activating protein 3 (IQGAP3) has been implicated in diverse cellular processes including neuronal morphogenesis, cell proliferation and motility as well as epithelial-mesenchymal transition. However, its roles in DNA damage and repair remain to be clarified. Here, we demonstrate that IQGAP3 is frequently overproduced and predicts poor prognosis in lung cancer patients. Functionally, we provide evidence that depletion of IQGAP3 impairs tumorigenesis and overcomes radioresistance in lung cancer in vitro and in vivo. Mechanistically, we uncover that IQGAP3 interacts with and controls the stability of Rad17 to activate the ATM/Chk2 signaling by recruiting Mre11-Rad50-Nbs1 (MRN) complex in response to DNA damage. Moreover, Rad17 is identified as the major downstream effector that mediates the functions of IQGAP3 in lung cancer. Clinically, IQGAP3 overexpression positively correlates with Rad17 protein levels in human lung cancer tissues. Collectively, these data support key roles for IQGAP3 in promoting tumorigenesis and radioresistance in lung cancer by stabilizing the Rad17 protein and suggest targeting IQGAP3 is a promising therapeutic strategy for lung cancer radiotherapy.
2019-09-21 | GSE137802 | GEO
Project description:We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach. Furthermore, we observed robust induction of IQGAP3 expression in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated expression of IQGAP3 in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes the upregulation of IQGAP3 in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both showing decreases during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon reexpression of IGF2BP1 during carcinogenesis. We found that IGF2BP1 binds and stabilizes m 6 A-modified IQGAP3 transcripts. Furthermore, downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.
2022-09-16 | GSE196405 | GEO
Project description:We reported earlier that IQGAP3 is an important stem cell factor in rapidly proliferating isthmus stem cells in the stomach. Furthermore, we observed robust induction of IQGAP3 expression in terminally differentiated chief cells and de-differentiated cells following tissue damage. The elevated expression of IQGAP3 in cancer and its association with metastasis suggest a fundamental role for IQGAP3 in proliferating cancer stem cells. What causes the upregulation of IQGAP3 in cancer is unclear. Here, we show that IGF2BP1 and IQGAP3 expression levels are highest in the blastocyst, with both showing decreases during adulthood. This suggests that IQGAP3, like IGF2BP1, is an early developmental gene that is aberrantly upregulated upon reexpression of IGF2BP1 during carcinogenesis. We found that IGF2BP1 binds and stabilizes m 6 A-modified IQGAP3 transcripts. Furthermore, downstream targets of IGF2BP1, namely SRF and FOXM1, also upregulate IQGAP3 expression. These multiple layers of IQGAP3 regulation, which may safeguard against inappropriate stem cell proliferation, present additional drug targets to inhibit IQGAP3-driven malignant growth.
2022-09-16 | GSE196238 | GEO
Project description:Objective: Tissue stem cells are central regulators of organ homeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus. Design: We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridization. We performed lineage tracing and transcriptomic analysis of Iqgap3+ isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumors from patient samples. Results: Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homeostasis. Iqgap3+ isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration. Conclusion: IQGAP3 is a major regulator of stomach epithelial tissue homeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
2021-03-08 | GSE161442 | GEO
Project description:Objective: Tissue stem cells are central regulators of organ homeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus. Design: We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridization. We performed lineage tracing and transcriptomic analysis of Iqgap3+ isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumors from patient samples. Results: Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homeostasis. Iqgap3+ isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration. Conclusion: IQGAP3 is a major regulator of stomach epithelial tissue homeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
2021-03-08 | GSE161443 | GEO
Project description:IQGAP3 interacts with Rad17 to activate the MRN/ATM/Chk2 signaling and promote radioresistance in lung cancer
| PRJNA573096 | ENA
Project description:The first is transcriptional profiling of siRNA-mediated knockdown of IQGAP3 in human gastric cancer cell line AGS, NUGC3, and Hs746T comparing with non-target siRNA transfected AGS, NUGC3, and Hs746T as a control. The aim of this experiment was to evaluate the functions of IQGAP3 in three different gastric cancer cell lines in vitro. The second is bulk RNA-sequence from subcutaneous tumors, which were injected NUGC3 shIQGAP3 knockdown cells and NUGC shContorl cells into immunodeficient mice (NSG mice). The aim is to evaluate the difference of transcriptional profiling in human cancer cells and mouse stromal cells of shIQGAP3 knockdown tumors compared to shContorol tumors.
2025-03-12 | GSE231642 | GEO