SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer

Aguilar‐Medina, Maribel; Avendaño-Félix, Mariana; Lizárraga-Verdugo, Erik; Bermúdez, Mercedes; Romero-Quintana, José Geovanni; Ramos-Payán, Rosalío; Ruiz‐García, Erika; López-Camarillo, César

doi:10.1155/2019/6754040

Cited by 76 publications

(66 citation statements)

References 156 publications

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“…Downstream of EGFRmut/BMX signaling, we have found an enrichment of SOX9 expression and protein stability. The oncogenic function of SOX9 has been proposed in different cancers (24), including gliomas (42,43), where it induces proliferation and cell survival, partly through BMI1 upregulation (44). Our data indicate that SOX9 also regulates the vascular properties of gliomas by inducing the cellular plasticity of tumor cells, which could be linked to its well-known effects in cancer stem cells (24).…”

Section: Discussionmentioning

confidence: 54%

“…SOX9 participates in a variety of functions during development, although it has also been implicated in the regulation of cancer stem cells (24). Moreover, we found a positive association of SOX9 with angiogenic processes in gliomas ( Figure 6D).…”

Section: Egfr Mutations Modulate the Vascular Properties Of Glioma Cementioning

confidence: 55%

“…The oncogenic function of SOX9 has been proposed in different cancers (24), including gliomas (42,43), where it induces proliferation and cell survival, partly through BMI1 upregulation (44). Our data indicate that SOX9 also regulates the vascular properties of gliomas by inducing the cellular plasticity of tumor cells, which could be linked to its well-known effects in cancer stem cells (24). Notably, SOX9 has been linked to the upregulation of PDGFR expression during development (45), and regulates genes involved in the extracellular matrix such as collagen, aggrecan and Timp1, which are involved in the maintenance of the blood vessel structure (46).…”

Section: Discussionmentioning

confidence: 99%

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The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

Segura-Collar

Garranzo‐Asensio

Herránz

et al. 2020

Preprint

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RationaleGlioma progression is driven by the induction of vascular alterations but how the tumor genotype influence these changes is still a pending issue. We propose to study the underlying mechanisms by which the genetic changes in isocitrate dehydrogenase 1/2 (IDH1/2) and epidermal growth factor receptor (EGFR) genes establish the different vascular profiles of gliomas.MethodsWe stratified gliomas based on the genetic status of IDH1/2 and EGFR genes. For that we used in silico data and a cohort of 93 glioma patients, where we analyzed the expression of several transcripts and proteins. For the in vitro and in vivo studies, we used a battery of primary glioblastoma cells derived from patients, as well as novel murine glioma cell lines expressing wild-type or mutant EGFR. In these models, the effect of the small molecule ibrutinib or the downregulation of CD248 and SOX9 was evaluated to establish a molecular mechanism.ResultsWe show that IDH1/2 mutations associate with a normalized vasculature. By contrast, EGFR mutations stimulate the plasticity of glioma cells and their capacity to function as pericytes in a bone-marrow and X-linked (BMX)/SOX9 dependent manner. The presence of tumor-derived pericytes stabilize the profuse vasculature and confers a growth advantage to these tumors, although they render them sensitive to pericyte-targeted molecules. Wild-type/amplified EGFR gliomas are enriched in blood vessels too, but they show a highly disrupted blood-brain-barrier due to a decreased BMX/SOX9 activation and pericyte coverage. This leads to poor nutrient supply, necrosis and hypoxia.ConclusionsThe function of tumor-derived pericytes delimitates two distinct and aggressive vascular phenotypes in IDH1/2 wild-type gliomas. Our results lay the foundations for a vascular dependent stratification of gliomas and suggest different therapeutic vulnerabilities depending on the genetic status of EGFR.Graphical Abstract. Schematic view of IDH and EGFR function in the regulation of glioma microenvironment.Mutant IDH gliomas express low levels of angiogenic molecules and have a vasculature reminiscent of normal tissue. EGFR mutations drive glioma growth by promoting tumor-to-pericyte transdifferentiation and vascular stabilization in a BMX-SOX9 dependent way. Leaky vessels with hypoxia and necrosis characterize tumors overexpressing the wild-type isoform of the receptor. These phenotypes determine the response to therapy of the different IDH wild-type gliomas.

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Section: Discussionmentioning

confidence: 54%

Section: Egfr Mutations Modulate the Vascular Properties Of Glioma Cementioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

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The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

Segura-Collar

Garranzo‐Asensio

Herránz

et al. 2020

Preprint

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“…RNA sequencing reveals that p62 and SOX9 are induced by IL-1 in LNCaP and MCF7 cells and are basally high in PC3 and MDA-MB-231 cells. p62 [20][21][22][23][24][25][26][27][28][29][30][31][32] and SOX9 [33][34][35][36][37][38][39] are overexpressed in both PCa and BCa patient tumor tissue, correlate with disease progression and treatment resistance, and support BCa and PCa tumor growth in vivo, indicating that these proteins are functional in cancer and clinically relevant.…”

Section: Introductionmentioning

confidence: 99%

IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα− BCa and AR− PCa cells and promotes cell survival

et al. 2020

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Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Thus, BCa and PCa patients are given therapies that reduce hormone levels or directly block HR activity; but most patients eventually develop treatment resistance. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERα and AR mRNA in HR-positive (HR +) BCa and PCa cell lines, yet the cells can remain viable. Additionally, we identified pro-survival proteins and processes upregulated by IL-1 in HR + BCa and PCa cells, that are basally high in HR − BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR + BCa and PCa cells that mimics conserved basal gene expression patterns in HR − BCa and PCa cells to promote HR-independent survival and tumorigenicity. Methods: We performed RNA sequencing (RNA-seq) for HR + BCa and PCa cell lines exposed to IL-1 and for untreated HR − BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in the BCa and PCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) and used the gene ontology web-based tool, GOrilla, to identify signaling pathways encoded by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR + cells that are, respectively, basally high or low in HR − cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR − BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in HR-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired hormone receptor independence and treatment resistance. We also assessed HR − cell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HR − cell lines. Conclusions: Our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic HR-independent BCa and PCa.

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“…RNA sequencing reveals that p62 and SOX9 are induced by IL-1 in LNCaP and MCF7 cells and are basally high in PC3 and MDA-MB-231 cells. p62 20,21,[30][31][32][22][23][24][25][26][27][28][29] and SOX9 [33][34][35][36][37][38][39] are overexpressed in both PCa and BCa patient tumor tissue, correlate with disease progression and treatment resistance, and support BCa and PCa tumor growth in vivo, indicating that these proteins are functional in cancer and clinically relevant.…”

mentioning

confidence: 99%

IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα- BCa and AR- PCa cells and promotes cell survival

Nawas¹,

Kanchwala

Thomas‐Jardin³

et al. 2020

Preprint

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Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Thus, BCa and PCa patients are given therapies that reduce hormone levels or directly block HR activity; but most patients eventually develop treatment resistance. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERα and AR mRNA in HR-positive (HR+) BCa and PCa cell lines, yet the cells can remain viable. Additionally, we identified pro-survival proteins and processes upregulated by IL-1 in HR+ BCa and PCa cells, that are basally high in HR- BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR+ BCa and PCa cells that mimics conserved basal gene expression patterns in HR- BCa and PCa cells to promote HR-independent survival and tumorigenicity. Methods: We performed RNA sequencing (RNA-seq) for HR+ BCa and PCa cell lines exposed to IL-1 and for untreated HR- BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in the BCa and PCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) and used the gene ontology web-based tool, GOrilla, to identify signaling pathways encoded by our RNA-seq data set. Results: We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR+ cells that are, respectively, basally high or low in HR- cells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR- BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in HR-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired hormone receptor independence and treatment resistance. We also assessed HR- cell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HR- cell lines. Conclusions: Our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic HR-independent BCa and PCa.

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SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer

Cited by 76 publications

References 156 publications

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

The genetic status of IDH1/2 and EGFR dictates the vascular landscape and the progression of gliomas

IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα− BCa and AR− PCa cells and promotes cell survival

IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα- BCa and AR- PCa cells and promotes cell survival

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