register interest

Dr Shazia Irshad

Research Area: Cell and Molecular Biology
Technology Exchange: Bioinformatics, Cell sorting, Computational biology, Flow cytometry, Immunohistochemistry, In situ hybridisation, In vivo imaging, Microscopy (Confocal), Microscopy (EM), Microscopy (Video), Protein interaction, Transcript profiling and Transgenesis
Scientific Themes: Cancer Biology and Physiology, Cellular & Molecular Biology
Keywords: Colorectal cancer metastasis

Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide. The high death rates in CRC as well as other solid tumours are mainly due to metastatic dissemination of cancer cells to distant organ sites. It is estimated that 50%–60% of patients diagnosed with CRC will develop metastasis. Metastasis is a complex multistep process that requires cells from the primary tumour to exhibit remarkable phenotypic plasticity at distant metastatic microenvironments for successful outgrowth. The understanding of underlying biological mechanisms involved in this metastatic transition is essential to identify critical nodes for clinical intervention to halt the disease in its progression. I am interested in investigating how the metastatic niche influences secondary tumor outgrowth by inducing cancer-promoting functions, such as proliferation, ECM remodeling, migration, invasion and angiogenesis. 

Name Department Institution Country
Professor Ian Tomlinson Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Simon Leedham Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Dr Mukesh Bansal Columbia University United States
Dr Paolo Guarnieri Columbia University United States
Dr Philipp Altrock Harvard United States
Irshad S, Bansal M, Guarnieri P, Davis H, Zen AAH, Baran B, Pinna CMA, Rahman H, Biswas S, Bardella C et al. 2017. Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer JOURNAL OF PATHOLOGY, 242 (2), pp. 178-192. | Show Abstract | Read more

© 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial–mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP–Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP–Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Irshad S, Bansal M, Guarnieri P, Davis H, Al Haj Zen A, Baran B, Pinna CMA, Rahman H, Biswas S, Bardella C et al. 2017. Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer. J Pathol, 242 (2), pp. 178-192. | Show Abstract | Read more

The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Biswas S, Davis H, Irshad S, Sandberg T, Worthley D, Leedham S. 2015. Microenvironmental control of stem cell fate in intestinal homeostasis and disease. J Pathol, 237 (2), pp. 135-145. | Show Abstract | Read more

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.

Mahul-Mellier A-L, Huc L, Lemarié A, Irshad S, Hwang M, Datler C, Pazarentzos E. 2015. Stefan Grimm, 1963-2014, a tragic loss for the scientific community. Cell Death Differ, 22 (2), pp. 247. | Read more

Biswas S, Davis H, Irshad S, Sandberg T, Worthley D, Leedham S. 2015. Microenvironmental control of stem cell fate in intestinal homeostasis and disease Journal of Pathology, 237 (2), pp. 135-145. | Show Abstract | Read more

© 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.

Cited:

57

Scopus

Davis H, Irshad S, Bansal M, Rafferty H, Boitsova T, Bardella C, Jaeger E, Lewis A, Freeman-Mills L, Giner FC et al. 2015. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche Nature Medicine, 21 (1), pp. 62-70. | Show Abstract | Read more

© 2014 Nature America, Inc. All rights reserved. Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Davis H, Irshad S, Bansal M, Rafferty H, Boitsova T, Bardella C, Jaeger E, Lewis A, Freeman-Mills L, Giner FC et al. 2015. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nat Med, 21 (1), pp. 62-70. | Show Abstract | Read more

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Irshad S, Bansal M, Castillo-Martin M, Zheng T, Aytes A, Wenske S, Le Magnen C, Guarnieri P, Sumazin P, Benson MC et al. 2013. A Correction to the Research Article Titled: "A Molecular Signature Predictive of Indolent Prostate Cancer" by S. Irshad, M. Bansal, M. Castillo-Martin, T. Zheng, A. Aytes, S. Wenske, C. Le Magnen, P. Guarnieri, P. Sumazin, M. C. Benson, M. M. Shen, A. Califano, C. Abate-Shen Science Translational Medicine, 5 (203), pp. 203er9-203er9. | Read more

Irshad S, Bansal M, Castillo-Martin M, Zheng T, Aytes A, Wenske S, Le Magnen C, Guarnieri P, Sumazin P, Benson MC et al. 2013. A molecular signature predictive of indolent prostate cancer. Sci Transl Med, 5 (202), pp. 202ra122. | Show Abstract | Read more

Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes--FGFR1, PMP22, and CDKN1A--that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.

Jin F, Irshad S, Yu W, Belakavadi M, Chekmareva M, Ittmann MM, Abate-Shen C, Fondell JD. 2013. ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity. Mol Cancer Res, 11 (7), pp. 736-747. | Show Abstract | Read more

MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.

Irshad S, Abate-Shen C. 2013. Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic. Cancer Metastasis Rev, 32 (1-2), pp. 109-122. | Show Abstract | Read more

More than 15 years ago, the first generation of genetically engineered mouse (GEM) models of prostate cancer was introduced. These transgenic models utilized prostate-specific promoters to express SV40 oncogenes specifically in prostate epithelium. Since the description of these initial models, there have been a plethora of GEM models of prostate cancer representing various perturbations of oncogenes or tumor suppressors, either alone or in combination. This review describes these GEM models, focusing on their relevance for human prostate cancer and highlighting their strengths and limitations, as well as opportunities for the future.

Irshad S, Mahul-Mellier A-L, Kassouf N, Lemarie A, Grimm S. 2009. Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers. Cell Death Differ, 16 (6), pp. 890-898. | Show Abstract | Read more

We have established a systematic high-throughput screen for genes that cause cell death specifically in transformed tumor cells. In a first round of screening, cDNAs that induce apoptosis in a transformed human cell line are detected. Positive genes are subsequently tested in a synthetic lethal screen in normal cells versus their isogenic counterparts that have been transformed by a particular oncogene. In this way, the organic cation transporter-like 3 (ORCTL3) gene was found to be inactive in normal rat kidney (NRK) cells, but to induce apoptosis in NRK cells transformed by oncogenic H-ras. ORCTL3 also causes cell death in v-src-transformed cells and in various human tumor cell lines but not in normal cells or untransformed cell lines. Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity. Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism. Finally, we detected ORCTL3 to be downregulated in human kidney tumors.

Budhram-Mahadeo VS, Irshad S, Bowen S, Lee SA, Samady L, Tonini GP, Latchman DS. 2008. Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells. Oncogene, 27 (1), pp. 145-154. | Show Abstract | Read more

Brn-3b transcription factor enhances proliferation of neuroblastoma (NB) and breast cancer cell lines in vitro and increases the rate and size of in vivo tumour growth, whereas reducing Brn-3b slows growth, both in vitro and in vivo. Brn-3b is elevated in >65% of breast cancer biopsies, and here we demonstrate that Brn-3b is also elevated in NB tumours. We show a significant correlation between Brn-3b and cyclin D1 (CD1) in breast cancers and NB tumours and cell lines. Brn-3b directly transactivates the CD1 promoter in co-transfection experiments, whereas electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrate that Brn-3b protein binds to an octamer sequence located in the proximal CD1 promoter. Site-directed mutagenesis of this sequence resulted in loss of transactivation of the CD1 promoter by Brn-3b. Thus, Brn-3b may act to alter growth properties of breast cancer and NB cells by enhancing CD1 expression in these cells.

Irshad S, Pedley RB, Anderson J, Latchman DS, Budhram-Mahadeo V. 2004. The Brn-3b transcription factor regulates the growth, behavior, and invasiveness of human neuroblastoma cells in vitro and in vivo. J Biol Chem, 279 (20), pp. 21617-21627. | Show Abstract | Read more

Neuroblastomas are the second most common solid tumor in children but the molecular mechanisms underlying the initiation and progression of this disease are poorly understood. We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate. In this study, we analyzed the effects of manipulating Brn-3b levels in the human neuroblastoma cell line, IMR-32 and showed that constitutive overexpression of Brn-3b consistently increased cellular growth and proliferation in monolayer as well as in an anchorage-independent manner compared with controls whereas stably decreasing Brn-3b can reduce the rate of growth of these cells. Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate. Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls. Interestingly, elevated Brn-3b levels also enhances the invasive capacity of these neuroblastoma cells with significantly larger numbers of migrating cells observed in overexpressing clones compared with controls. Because invasion and metastasis influence morbidity and mortality in neuroblastoma and so significantly affect the course and outcome of neuroblastomas, this finding is very important. Our results therefore suggest that Brn-3b transcription factor contributes to proliferation of neuroblastoma cells in vivo and in vitro but may also influence progression and/or invasion during tumorigenesis. It is possible that decreasing Brn-3b levels may reverse some effects on growth and proliferation of these cells.

Budhram-Mahadeo V, Morris P, Ndisang D, Irshad S, Lozano G, Pedley B, Latchman DS. 2002. The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells. Neurosci Lett, 334 (1), pp. 1-4. | Show Abstract | Read more

The Brn-3a POU family transcription factor is able to induce the expression of genes encoding anti-apoptotic proteins such as Bcl-2 and Bcl-x and protects neuronal cells from apoptosis. This effect is opposed by the pro-apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters. Here we demonstrate that Brn-3a is able to stimulate p53 expression. Thus, in co-transfection experiments, Brn-3a activates the p53 promoter acting via a region from +22 to +67, located between the most proximal (+1) and the most distal (+105) transcriptional start sites. Similarly, reduction of Brn-3a expression using anti-sense constructs reduces endogenous p53 expression in human neuroblastoma or cervical carcinoma cell lines growing in vitro and as tumours in nude mice whilst increasing Brn-3a levels enhances p53 expression. These results suggest the existence of a negative feedback loop in which elevated Brn-3a expression induces the expression of p53 which, in turn, antagonises the anti-apoptotic activity of Brn-3a.

Biswas S, Davis H, Irshad S, Sandberg T, Worthley D, Leedham S. 2015. Microenvironmental control of stem cell fate in intestinal homeostasis and disease. J Pathol, 237 (2), pp. 135-145. | Show Abstract | Read more

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.

Cited:

57

Scopus

Davis H, Irshad S, Bansal M, Rafferty H, Boitsova T, Bardella C, Jaeger E, Lewis A, Freeman-Mills L, Giner FC et al. 2015. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche Nature Medicine, 21 (1), pp. 62-70. | Show Abstract | Read more

© 2014 Nature America, Inc. All rights reserved. Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Irshad S, Bansal M, Castillo-Martin M, Zheng T, Aytes A, Wenske S, Le Magnen C, Guarnieri P, Sumazin P, Benson MC et al. 2013. A Correction to the Research Article Titled: "A Molecular Signature Predictive of Indolent Prostate Cancer" by S. Irshad, M. Bansal, M. Castillo-Martin, T. Zheng, A. Aytes, S. Wenske, C. Le Magnen, P. Guarnieri, P. Sumazin, M. C. Benson, M. M. Shen, A. Califano, C. Abate-Shen Science Translational Medicine, 5 (203), pp. 203er9-203er9. | Read more

Jin F, Irshad S, Yu W, Belakavadi M, Chekmareva M, Ittmann MM, Abate-Shen C, Fondell JD. 2013. ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity. Mol Cancer Res, 11 (7), pp. 736-747. | Show Abstract | Read more

MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.

Irshad S, Abate-Shen C. 2013. Modeling prostate cancer in mice: something old, something new, something premalignant, something metastatic. Cancer Metastasis Rev, 32 (1-2), pp. 109-122. | Show Abstract | Read more

More than 15 years ago, the first generation of genetically engineered mouse (GEM) models of prostate cancer was introduced. These transgenic models utilized prostate-specific promoters to express SV40 oncogenes specifically in prostate epithelium. Since the description of these initial models, there have been a plethora of GEM models of prostate cancer representing various perturbations of oncogenes or tumor suppressors, either alone or in combination. This review describes these GEM models, focusing on their relevance for human prostate cancer and highlighting their strengths and limitations, as well as opportunities for the future.

Irshad S, Mahul-Mellier A-L, Kassouf N, Lemarie A, Grimm S. 2009. Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers. Cell Death Differ, 16 (6), pp. 890-898. | Show Abstract | Read more

We have established a systematic high-throughput screen for genes that cause cell death specifically in transformed tumor cells. In a first round of screening, cDNAs that induce apoptosis in a transformed human cell line are detected. Positive genes are subsequently tested in a synthetic lethal screen in normal cells versus their isogenic counterparts that have been transformed by a particular oncogene. In this way, the organic cation transporter-like 3 (ORCTL3) gene was found to be inactive in normal rat kidney (NRK) cells, but to induce apoptosis in NRK cells transformed by oncogenic H-ras. ORCTL3 also causes cell death in v-src-transformed cells and in various human tumor cell lines but not in normal cells or untransformed cell lines. Although ORCTL3 is a member of the organic cation transporter gene family, our data indicate that this gene induces apoptosis independently of its putative transporter activity. Rather, various lines of evidence suggest that ORCTL3 brings about apoptosis by an endoplasmic reticulum stress-mediated mechanism. Finally, we detected ORCTL3 to be downregulated in human kidney tumors.

Budhram-Mahadeo VS, Irshad S, Bowen S, Lee SA, Samady L, Tonini GP, Latchman DS. 2008. Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells. Oncogene, 27 (1), pp. 145-154. | Show Abstract | Read more

Brn-3b transcription factor enhances proliferation of neuroblastoma (NB) and breast cancer cell lines in vitro and increases the rate and size of in vivo tumour growth, whereas reducing Brn-3b slows growth, both in vitro and in vivo. Brn-3b is elevated in >65% of breast cancer biopsies, and here we demonstrate that Brn-3b is also elevated in NB tumours. We show a significant correlation between Brn-3b and cyclin D1 (CD1) in breast cancers and NB tumours and cell lines. Brn-3b directly transactivates the CD1 promoter in co-transfection experiments, whereas electrophoretic mobility shift assay and chromatin immunoprecipitation assays demonstrate that Brn-3b protein binds to an octamer sequence located in the proximal CD1 promoter. Site-directed mutagenesis of this sequence resulted in loss of transactivation of the CD1 promoter by Brn-3b. Thus, Brn-3b may act to alter growth properties of breast cancer and NB cells by enhancing CD1 expression in these cells.

Irshad S, Pedley RB, Anderson J, Latchman DS, Budhram-Mahadeo V. 2004. The Brn-3b transcription factor regulates the growth, behavior, and invasiveness of human neuroblastoma cells in vitro and in vivo. J Biol Chem, 279 (20), pp. 21617-21627. | Show Abstract | Read more

Neuroblastomas are the second most common solid tumor in children but the molecular mechanisms underlying the initiation and progression of this disease are poorly understood. We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate. In this study, we analyzed the effects of manipulating Brn-3b levels in the human neuroblastoma cell line, IMR-32 and showed that constitutive overexpression of Brn-3b consistently increased cellular growth and proliferation in monolayer as well as in an anchorage-independent manner compared with controls whereas stably decreasing Brn-3b can reduce the rate of growth of these cells. Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate. Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls. Interestingly, elevated Brn-3b levels also enhances the invasive capacity of these neuroblastoma cells with significantly larger numbers of migrating cells observed in overexpressing clones compared with controls. Because invasion and metastasis influence morbidity and mortality in neuroblastoma and so significantly affect the course and outcome of neuroblastomas, this finding is very important. Our results therefore suggest that Brn-3b transcription factor contributes to proliferation of neuroblastoma cells in vivo and in vitro but may also influence progression and/or invasion during tumorigenesis. It is possible that decreasing Brn-3b levels may reverse some effects on growth and proliferation of these cells.

Budhram-Mahadeo V, Morris P, Ndisang D, Irshad S, Lozano G, Pedley B, Latchman DS. 2002. The Brn-3a POU family transcription factor stimulates p53 gene expression in human and mouse tumour cells. Neurosci Lett, 334 (1), pp. 1-4. | Show Abstract | Read more

The Brn-3a POU family transcription factor is able to induce the expression of genes encoding anti-apoptotic proteins such as Bcl-2 and Bcl-x and protects neuronal cells from apoptosis. This effect is opposed by the pro-apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters. Here we demonstrate that Brn-3a is able to stimulate p53 expression. Thus, in co-transfection experiments, Brn-3a activates the p53 promoter acting via a region from +22 to +67, located between the most proximal (+1) and the most distal (+105) transcriptional start sites. Similarly, reduction of Brn-3a expression using anti-sense constructs reduces endogenous p53 expression in human neuroblastoma or cervical carcinoma cell lines growing in vitro and as tumours in nude mice whilst increasing Brn-3a levels enhances p53 expression. These results suggest the existence of a negative feedback loop in which elevated Brn-3a expression induces the expression of p53 which, in turn, antagonises the anti-apoptotic activity of Brn-3a.

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