Overview
Dr Allard received a BSc (Hons) in Cellular and Molecular Pathology from the University of Bristol and completed a PhD in Cancer Studies at the University of Liverpool studying the regulation of the metastasis gene S100A4. Subsequently Dr Allard worked as a postdoctoral fellow at the ICRF in Cambridge (Prof Gherardi and Sir Stoker FRS) where he developed his interest in the role of cell-cell interactions in determining cancer progression. An interest in cell-cell interactions in disease settings was developed by postdoctoral studies in the department of Medicine, Cambridge University (Prof Bennett) and the CR:UK Cambridge Research Institute (Prof Tuveson). In 2011, Dr Allard moved to the University of Exeter to set up a group studying the cell biology of disease. Dr Allard’s research interests are in the molecular and cell biology of disease progression, particularly cancer.
Qualifications
BSc (Hons) Bristol
PhD Liverpool
FHEA
Research group links
Research
Research interests
Cell and Molecular biology of tumour progression.
Although cancer is the second most common cause of death in the UK, there are many mechanisms by which tumour progression is controlled. These include genetic and epigenetic alterations in the cancer cell and interactions between the cancer cell and surrounding cells, the tumour microenvironment. We study the role of the tumour microenvironment in suppressing the growth of tumour cells. A major part of our work is determining the molecular signals at the cell surface through which control of tumour cell fate is determined by the microenvironment. Complementary projects aim to identify the molecules within the tumour cell through which these signals are transmitted to initiate this form of growth arrest.
The approaches we use are both a targeted investigation of candidate genes and unbiased screening (e.g. with shRNA libraries) for functional genes. Gene expression is affected in cells found in the tumour microenvironment and the effect on the growth of surrounding cancer cells evaluated using high-throughput microscopy or next generation sequencing.
These studies are performed in collaboration with Professor Tuveson (CSHL), Professors Georg Klein and Laszlo Szerkely (Karolinska institute, Sweden) and Professor Gherardi (Italy).
Pancreatic beta cell biology.
Diabetes is characterised by the loss of pancreatic beta cell function, either through death of beta cells or through the reduced ability of beta cells to secrete insulin. We aim to identify novel genes that either protect pancreatic beta cells from death or increase insulin secretion. Subsequently, the products of these genes may be amenable to the development of therapeutic intervention strategies. These studies are complemented by functional analysis of SNPs associated with diabetic phenotypes identified in GWAS studies either directly or indirectly through comparison of GWAS and functional screen data.
In collaboration with Professor Tim Frayling (UEMS).
Research projects
Role of cell-cell interactions in tumour initiation and progression
• High throughput microscopic screening for genes involved in non-cell autonomous control of cancer progression
• Identification of novel genes involved in the tumour microenvironment through next generation sequencing.
• Role of the extracellular matrix enzymes in tumour initiation and progression
Beta cell biology
• Identification of novel genes controlling pancreatic beta cell proliferation and death through next generation sequencing based screening approaches
• Identification of novel genes involved in secretion of insulin from beta cells through high-throughput microscopy
• The role of genes identified by GWAS in pancreatic beta cell function
Research networks
Professor Gherardi (University of Pavia)
Professors Klein and Szekely (Karolinska Institute, Sweden)
Publications
Key publications | Publications by category | Publications by year
Publications by category
Journal articles
Azevedo-Pouly ACP, Sutaria DS, Jiang J, Elgamal OA, Amari F, Allard D, Grippo PJ, Coppola V, Schmittgen TD (2017). miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.
Functional and Integrative Genomics,
17(2-3), 203-212.
Abstract:
miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal
Mice harboring a G12D activating Kras mutation are among the most heavily studied models in the field of pancreatic adenocarcinoma (PDAC) research. miRNAs are differentially expressed in PDAC from patients and mouse models of PDAC. To better understand the relationship that Kras activation has on miRNA expression, we profiled the expression of 629 miRNAs in RNA isolated from the pancreas of control, young, and old P48+/Cre;LSL-KRASG12D as well as PDX-1-Cre;LSL-KRASG12D mice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48+/Cre;LSL-KRASG12D compared to wild-type mice. Interestingly, the expression of three miRNAs, miR-216a, miR-216b, and miR-217, located within a ∼30-kbp region on 11qA3.3, decreased with age (and phenotype severity) in these mice. miR-216/-217 expression was also evaluated in another acinar-specific ELa-KrasG12D mouse model and was downregulated as well. As miR-216/-217 are acinar enriched, reduced in human PDAC and target KRAS, we hypothesized that they may maintain acinar differentiation or represent tumor suppressive miRNAs. To test this hypothesis, we deleted a 27.9-kbp region of 11qA3.3 containing the miR-216/-217 host gene in the mouse’s germ line. We report that germ line deletion of this cluster is embryonic lethal in the mouse. We estimate that lethality occurs shortly after E9.5. qPCR analysis of the miR-216b and miR-217 expression in the heterozygous animals showed no difference in expression, suggesting haplosufficiency by some type of compensatory mechanism. We present the differential miRNA expression in KrasG12D transgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse’s germ line.
Abstract.
Jiang J, Azevedo-Pouly ACP, Redis RS, Lee EJ, Gusev Y, Allard D, Sutaria DS, Badawi M, Elgamal OA, Lerner MR, et al (2016). Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma.
Oncotarget,
7(33), 53165-53177.
Abstract:
Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma.
Transcribed ultraconserved regions (T-UCRs) are a class of non-coding RNAs with 100% sequence conservation among human, rat and mouse genomes. T-UCRs are differentially expressed in several cancers, however their expression in pancreatic adenocarcinoma (PDAC) has not been studied. We used a qPCR array to profile all 481 T-UCRs in pancreatic cancer specimens, pancreatic cancer cell lines, during experimental pancreatic desmoplasia and in the pancreases of P48Cre/wt; KrasLSL-G12D/wt mice. Fourteen, 57 and 29% of the detectable T-UCRs were differentially expressed in the cell lines, human tumors and transgenic mouse pancreases, respectively. The vast majority of the differentially expressed T-UCRs had increased expression in the cancer. T-UCRs were monitored using an in vitro model of the desmoplastic reaction. Twenty-five % of the expressed T-UCRs were increased in the HPDE cells cultured on PANC-1 cellular matrix. UC.190, UC.233 and UC.270 were increased in all three human data sets. siRNA knockdown of each of these three T-UCRs reduced the proliferation of MIA PaCa-2 cells up to 60%. The expression pattern among many T-UCRs in the human and mouse pancreases closely correlated with one another, suggesting that groups of T-UCRs are co-activated in PDAC. Successful knockout of the transcription factor EGR1 in PANC-1 cells caused a reduction in the expression of a subset of T-UCRs suggesting that EGR1 may control T-UCR expression in PDAC. We report a global increase in expression of T-UCRs in both human and mouse PDAC. Commonalties in their expression pattern suggest a similar mechanism of transcriptional upregulation for T-UCRs in PDAC.
Abstract.
Author URL.
Azevedo ACP, Jiang J, Lee EJ, Gusev Y, Allard D, Tuveson DA, Calin GA, Schmittgen TD (2011). Global increase in ultraconserved non-coding RNA expression in pancreatic adenocarcinoma.
CANCER RESEARCH,
71 Author URL.
Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, et al (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
Science,
324(5933), 1457-1461.
Abstract:
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
Abstract.
Author URL.
Allard D, Figg N, Bennett MR, Littlewood TD (2008). Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3.
J Biol Chem,
283(28), 19739-19747.
Abstract:
Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3.
Apoptosis of vascular smooth muscle cells (VSMCs) may lead to atherosclerotic plaque instability and rupture, resulting in myocardial infarction, stroke, and sudden death. However, the molecular mechanisms mediating survival of VSMCs in atherosclerotic plaques remain unknown. Although plaque VSMCs exhibit increased susceptibility to apoptosis and reduced expression of the IGF1 receptor (IGF1R) when compared with normal VSMCs, a causative effect has not been established. Here we show that increased expression of the IGF1R can rescue plaque VSMCs from oxidative stress-induced apoptosis, demonstrating that IGF-1 signaling is a critical regulator of VSMC survival. Akt mediates the majority of the IGF1R survival signaling, and ectopic activation of Akt was sufficient to protect VSMCs in vitro. Both IGF1R and phospho-Akt expression were reduced in human plaque (intimal) VSMCs when compared with medial VSMCs, suggesting that Akt mediates survival signaling in atherosclerosis. Importantly, downstream targets of Akt were identified that mediate its protective effect as inhibition of FoxO3a or GSK3 by Akt-dependent phosphorylation protected VSMCs in vitro. We conclude that Akt and its downstream targets FoxO3a and GSK3 regulate a survival pathway in VSMCs and that their deregulation due to a reduction of IGF1R signaling may promote apoptosis in atherosclerosis.
Abstract.
Author URL.
Allard D, Stoker M, Gherardi E (2003). A G2/M cell cycle block in transformed cells by contact with normal neighbors.
Cell Cycle,
2(5), 484-487.
Abstract:
A G2/M cell cycle block in transformed cells by contact with normal neighbors.
Neighbour suppression of growth of tumour cells by stationary normal cells might be important in early stages of cancer. We have studied this using suppressor and non-suppressor lines of 3T3 fibroblasts and SV40 transformed derivatives. Growth suppression of transformed cells depended on direct contact with stationary confluent cultures of 3T3 cells but not on gap junction communication. It was not caused by apoptosis nor through the normal G0/G1 block present in the confluent normal cells. Instead, there was a progressive elongation of the cell cycle leading to arrest in G2/M in the transformed cells. This indicates an unusual type of growth arrest not previously involved in social control of cell growth.
Abstract.
Author URL.
Conferences
Allard DJ, Figg N, Bennett MR, Littlewood TD (2007). Akt-mediated inhibition of apotosis in vascular smooth muscle cells.
Author URL.
Publications by year
2017
Azevedo-Pouly ACP, Sutaria DS, Jiang J, Elgamal OA, Amari F, Allard D, Grippo PJ, Coppola V, Schmittgen TD (2017). miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.
Functional and Integrative Genomics,
17(2-3), 203-212.
Abstract:
miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal
Mice harboring a G12D activating Kras mutation are among the most heavily studied models in the field of pancreatic adenocarcinoma (PDAC) research. miRNAs are differentially expressed in PDAC from patients and mouse models of PDAC. To better understand the relationship that Kras activation has on miRNA expression, we profiled the expression of 629 miRNAs in RNA isolated from the pancreas of control, young, and old P48+/Cre;LSL-KRASG12D as well as PDX-1-Cre;LSL-KRASG12D mice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48+/Cre;LSL-KRASG12D compared to wild-type mice. Interestingly, the expression of three miRNAs, miR-216a, miR-216b, and miR-217, located within a ∼30-kbp region on 11qA3.3, decreased with age (and phenotype severity) in these mice. miR-216/-217 expression was also evaluated in another acinar-specific ELa-KrasG12D mouse model and was downregulated as well. As miR-216/-217 are acinar enriched, reduced in human PDAC and target KRAS, we hypothesized that they may maintain acinar differentiation or represent tumor suppressive miRNAs. To test this hypothesis, we deleted a 27.9-kbp region of 11qA3.3 containing the miR-216/-217 host gene in the mouse’s germ line. We report that germ line deletion of this cluster is embryonic lethal in the mouse. We estimate that lethality occurs shortly after E9.5. qPCR analysis of the miR-216b and miR-217 expression in the heterozygous animals showed no difference in expression, suggesting haplosufficiency by some type of compensatory mechanism. We present the differential miRNA expression in KrasG12D transgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse’s germ line.
Abstract.
2016
Jiang J, Azevedo-Pouly ACP, Redis RS, Lee EJ, Gusev Y, Allard D, Sutaria DS, Badawi M, Elgamal OA, Lerner MR, et al (2016). Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma.
Oncotarget,
7(33), 53165-53177.
Abstract:
Globally increased ultraconserved noncoding RNA expression in pancreatic adenocarcinoma.
Transcribed ultraconserved regions (T-UCRs) are a class of non-coding RNAs with 100% sequence conservation among human, rat and mouse genomes. T-UCRs are differentially expressed in several cancers, however their expression in pancreatic adenocarcinoma (PDAC) has not been studied. We used a qPCR array to profile all 481 T-UCRs in pancreatic cancer specimens, pancreatic cancer cell lines, during experimental pancreatic desmoplasia and in the pancreases of P48Cre/wt; KrasLSL-G12D/wt mice. Fourteen, 57 and 29% of the detectable T-UCRs were differentially expressed in the cell lines, human tumors and transgenic mouse pancreases, respectively. The vast majority of the differentially expressed T-UCRs had increased expression in the cancer. T-UCRs were monitored using an in vitro model of the desmoplastic reaction. Twenty-five % of the expressed T-UCRs were increased in the HPDE cells cultured on PANC-1 cellular matrix. UC.190, UC.233 and UC.270 were increased in all three human data sets. siRNA knockdown of each of these three T-UCRs reduced the proliferation of MIA PaCa-2 cells up to 60%. The expression pattern among many T-UCRs in the human and mouse pancreases closely correlated with one another, suggesting that groups of T-UCRs are co-activated in PDAC. Successful knockout of the transcription factor EGR1 in PANC-1 cells caused a reduction in the expression of a subset of T-UCRs suggesting that EGR1 may control T-UCR expression in PDAC. We report a global increase in expression of T-UCRs in both human and mouse PDAC. Commonalties in their expression pattern suggest a similar mechanism of transcriptional upregulation for T-UCRs in PDAC.
Abstract.
Author URL.
2011
Azevedo ACP, Jiang J, Lee EJ, Gusev Y, Allard D, Tuveson DA, Calin GA, Schmittgen TD (2011). Global increase in ultraconserved non-coding RNA expression in pancreatic adenocarcinoma.
CANCER RESEARCH,
71 Author URL.
2009
Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, et al (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
Science,
324(5933), 1457-1461.
Abstract:
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
Abstract.
Author URL.
2008
Allard D, Figg N, Bennett MR, Littlewood TD (2008). Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3.
J Biol Chem,
283(28), 19739-19747.
Abstract:
Akt regulates the survival of vascular smooth muscle cells via inhibition of FoxO3a and GSK3.
Apoptosis of vascular smooth muscle cells (VSMCs) may lead to atherosclerotic plaque instability and rupture, resulting in myocardial infarction, stroke, and sudden death. However, the molecular mechanisms mediating survival of VSMCs in atherosclerotic plaques remain unknown. Although plaque VSMCs exhibit increased susceptibility to apoptosis and reduced expression of the IGF1 receptor (IGF1R) when compared with normal VSMCs, a causative effect has not been established. Here we show that increased expression of the IGF1R can rescue plaque VSMCs from oxidative stress-induced apoptosis, demonstrating that IGF-1 signaling is a critical regulator of VSMC survival. Akt mediates the majority of the IGF1R survival signaling, and ectopic activation of Akt was sufficient to protect VSMCs in vitro. Both IGF1R and phospho-Akt expression were reduced in human plaque (intimal) VSMCs when compared with medial VSMCs, suggesting that Akt mediates survival signaling in atherosclerosis. Importantly, downstream targets of Akt were identified that mediate its protective effect as inhibition of FoxO3a or GSK3 by Akt-dependent phosphorylation protected VSMCs in vitro. We conclude that Akt and its downstream targets FoxO3a and GSK3 regulate a survival pathway in VSMCs and that their deregulation due to a reduction of IGF1R signaling may promote apoptosis in atherosclerosis.
Abstract.
Author URL.
2007
Allard DJ, Figg N, Bennett MR, Littlewood TD (2007). Akt-mediated inhibition of apotosis in vascular smooth muscle cells.
Author URL.
2003
Allard D, Stoker M, Gherardi E (2003). A G2/M cell cycle block in transformed cells by contact with normal neighbors.
Cell Cycle,
2(5), 484-487.
Abstract:
A G2/M cell cycle block in transformed cells by contact with normal neighbors.
Neighbour suppression of growth of tumour cells by stationary normal cells might be important in early stages of cancer. We have studied this using suppressor and non-suppressor lines of 3T3 fibroblasts and SV40 transformed derivatives. Growth suppression of transformed cells depended on direct contact with stationary confluent cultures of 3T3 cells but not on gap junction communication. It was not caused by apoptosis nor through the normal G0/G1 block present in the confluent normal cells. Instead, there was a progressive elongation of the cell cycle leading to arrest in G2/M in the transformed cells. This indicates an unusual type of growth arrest not previously involved in social control of cell growth.
Abstract.
Author URL.
Refresh publications
Teaching
Dr Allard is a co-module lead on the BSc (Hons) Medical Sciences program for the core final year module (Integrated Clinical Sciences 4), is the theme lead for Cell biology within the Medical School and teaches various aspects of both the BSc (Hons) Medical Sciences and BMBS programs.
Modules
2022/23
Information not currently available
Supervision / Group
Postgraduate researchers
- Lorena Boquete-Vilarino
- Ashley Nicholls
Alumni
- Emma Dearing underggraduate project
- Jade Lyons-Rimmer undergraduate project
- Richard Perryman undergraduate project
- Katarzyna Wolanska research associate
