Dissecting roles of High Mobility Group A1 (HMGA1) pathway in pancreatic adenocarcinoma progression through in vivo monitoring of cancer dynamics...

Lead Research Organisation: University of Cambridge
Department Name: Surgery

Abstract

Pancreatic cancer is the deadliest of human cancers. Effective treatment and early detection strategies for this cancer is desperately needed. Our project aims to understand the process of pancreatic cancer progression, in the hope of identifying new ways to treat and detect this cancer. By focussing on the roles of high mobility group A1 (HMGA1) gene, we may identify novel pathways for rational therapy of pancreatic cancer. Our project may lead to the development of imaging-based early detection strategies.

Technical Summary

Introduction: Pancreatic ductal adenocarcinoma (PDA) is the 5th leading cause of cancer-related death in the UK. To improve our understanding of this deadly cancer, we have engineered the KPC mouse harbouring conditional mutant alleles in K-ras and p53 genes targeted exclusively to pancreas, which recapitulates PDA (100% penetrance). The HMGA1 gene encodes for chromatin-associated proteins which regulate a constellation of pro-oncogenic genes. Our data suggests that HMGA1 is overexpressed in >90% of PDAs. Previously, we showed that HMGA1 promotes malignant phenotype in PDA cells. We now propose to dissect the roles of HMGA1 in PDA progression.

Project aims: We have formulated 3 independent study aims.

Aim-1: To examine the process of PDA progression in real-time by in vivo introduction of pro-oncogenic HMGA1 coexpressed with a fluorescent reporter
We hypothesize that in vivo introduction of HMGA1 gene will accelerate the process of cancer progression in KPC murine pancreas. We will introduce the HMGA1 gene coexpressed with a reporter gene (i.e. eGFP) into the pancreas of KPC mouse. At the site of HMGA1-eGFP introduction, the developing PDA will be labeled with eGFP which allows imaging studies (intravital multiphoton microscopy, bioluminescence) to track tumour progression, at an unprecedented single-cell level in vivo.

Aim-2: To evaluate if HMGA1 promotes initiation and maintenance of PDA using a conditional transgenic mouse model
We will perform a genetic dissection of HMGA1 functions using 3 novel targeted mouse models: conditional knock-in (CKI-1 &-2) and conditional knockout (CKO) HMGA1 mice. We will assess the dependence of PDA initiation and maintenance on HMGA1 expression. Co-operative roles of HMGA1 with K-ras and p53 will be elucidated by crossing the HMGA1 transgenic mice (CKI-1, CKI-2, CKO) with KPC mice.

Aim-3: To perform a genome-wide analysis of HMGA1 transcriptional and signaling networks in PDA to identify novel biomarkers and therapeutic targets
Using chromatin immunoprecipitation sequencing (ChIP-Seq), microarray expression profiling and constructed PanIN-PDA tissue microarrays, we will systematically examine integrated HMGA1-related pathways to identify ‘direct‘ and ‘indirect‘ targets of HMGA1. Harnessing bioinformatic strategies, we will focus on clinically-relevant candidate pathways of functional importance to identify novel biomarkers and therapeutic targets.

Medical Opportunities: Our research strategy of characterising the mechanisms driving PDA progression will yield rational therapies and new biomarkers for early detection of this deadly cancer.

Publications

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Al-Adra DP (2015) Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis. in European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology

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Ali JM (2012) Laparoscopic adrenalectomy: auditing the 10 year experience of a single centre. in The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland

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Chatzizacharias NA (2017) Surgical management of hepato-pancreatic metastasis from renal cell carcinoma. in World journal of gastrointestinal oncology

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Liau SS (2013) Molecular pathogenesis of hepatic adenomas and its implications for surgical management. in Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract

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Siong-Seng Liau And David Tuveson (2014) Molecular pathology of pancreatic cancer

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Zelga P (2015) Negative predictive value of drain amylase concentration for development of pancreatic fistula after pancreaticoduodenectomy. in Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]

 
Guideline Title European Society of Medical Oncology (ESMO) Biliary Cancer Guidelines Indicate Selective Internal Radiation Therapy (SIRT) with Y-90 Microspheres as an Option for Post-Chemotherapy Treatment of Intrahepatic Cholangiocarcinoma (iCCA)
Description Utilisation of recent publication as basis of new European Society of Medical Oncology (ESMO) Biliary Cancer Guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The following excerpt was obtained from ESMO: ''The ESMO inclusion of SIRT for the treatment of iCCA was based on ESMO's review of a pooled analysis of 12 studies totalling 298 patients that was published in the European Journal of Surgical Oncology in 2015, by Dr D. Al-Adra et al. These data showed a median overall survival of 15.5 months and treatment response rate of 28% in patients treated with SIRT. In addition, the new ESMO guidelines on biliary cancers call special attention to a subset of studies in the pooled SIRT analysis, stating that importantly, 7/73 (10%) patients in three selected studies were converted to resectable disease, highlighting the importance of reassessment of patients in the multidisciplinary team in the event of a good response to any treatment."
URL http://www.prnewswire.co.uk/news-releases/new-european-society-of-medical-oncology-esmo-biliary-canc...
 
Description MRC Early Career Centenary Award
Amount £2,600 (GBP)
Organisation Hutchison/MRC Research Centre 
Sector Multiple
Country United Kingdom
Start 01/2013 
End 12/2013
 
Description Pancreatic Society of Great Britain and Ireland Pump-priming Research Grant
Amount £10,000 (GBP)
Organisation Pancreatic Society of Great Britain and Ireland (PanSoc) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 01/2016
 
Description Pump Priming Grant
Amount £10,000 (GBP)
Organisation Royal College of Surgeons of England 
Sector Learned Society
Country United Kingdom
Start 01/2015 
End 01/2016
 
Description RCS Edinburgh Small Research Grant
Amount £10,000 (GBP)
Organisation The Royal College of Surgeons of Edinburgh 
Sector Learned Society
Country United Kingdom
Start 01/2014 
End 01/2017
 
Description RCS Edinburgh Small Research Grant
Amount £10,000 (GBP)
Organisation The Royal College of Surgeons of Edinburgh 
Sector Learned Society
Country United Kingdom
Start 09/2016 
End 09/2017
 
Description Small Research Grant
Amount £7,000 (GBP)
Organisation The Royal College of Surgeons of Edinburgh 
Sector Learned Society
Country United Kingdom
Start 09/2011 
End 09/2012
 
Description Starter Grant
Amount £30,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2010 
End 09/2012
 
Title Transgenic mouse models of pancreatic cancer based on Aurora A kinase mutation 
Description Mouse models of pancreatic cancer based on transgenic expression of mutant Aurora A kinase. These models have been successfully developed. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Once developed, these mouse models will facilitate the study of gene functions in the development of pancreatic cancer. 
 
Title Transgenic mouse models of pancreatic cancer based on Palb2 mutation 
Description Mouse models of pancreatic cancer based on mutant Palb2 gene. These models have been successfully developed. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact nce developed, these mouse models will facilitate the study of gene functions in the development of pancreatic cancer. 
 
Title Database of post-resection pancreatic cancer patients in East Anglia with linked clinical and survival outcome based on UK Cancer Registry data 
Description We have retrospectively collected the data for a large cohort of patients who had undergone pancreatic resection for malignancies at Cambridge HPB Surgical Unit over the last 10 years, with the primary aim of identifying the survival outcome and factors that influence survivals. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Research manuscript is current in progress. 
 
Description Collaboration With Dr Rebecca Brais 
Organisation Addenbrooke's Hospital
Department Histopathology Department
Country United Kingdom 
Sector Hospitals 
PI Contribution Analysis of pancreatic cancer tissue microarray.
Collaborator Contribution Provision of pancreatic cancer tissue microarray and the use of the Department of Histopathology Research Core for IHC.
Impact Histopathology and Surgery.
Start Year 2012
 
Description Collaboration with Angle Plc. 
Organisation ANGLE
Department Parsotix Team
Country United Kingdom 
Sector Private 
PI Contribution Collaboratively, we are assisting with the intellectual and scientific development of this novel patented Parstotix Circulating Tumour Cell (CTC) capture device (based on separation by physical characteristics of CTCs) and the analyser system. We will assist in the development of this system into one with clinical utility in cancer patients, specifically in pancreatic cancer.
Collaborator Contribution Collaboratively, we are assisting with the intellectual and scientific development of this novel patented Parstotix Circulating Tumour Cell (CTC) capture device (based on separation by physical characteristics of CTCs) and the analyser system. We will assist in the development of this system into one with clinical utility in cancer patients, specifically in pancreatic cancer.
Impact Ongoing
Start Year 2013
 
Description Collaboration with Dr Anguraj Sadanandam 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution We have provided whole genome and RNA-seq data from pancreatic cancer tumour cell lines generated from our novel transgenic mouse models.
Collaborator Contribution Dr Sadanandam's team will be collaborating with us to analyse the genetic landscape of DNA-repair deficient pancreatic cancers.
Impact Yes, the collaboration is ongoing and multi-disciplinary as it involves laboratory research (molecular oncology) and bioinformatics.
Start Year 2017
 
Description Collaboration with Dr Doug Fearon 
Organisation Cancer Research UK Cambridge Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborating as a surgeon scientist
Collaborator Contribution Cancer immunology
Impact Surgical oncology and cancer immunology
Start Year 2014
 
Description Collaboration with Dr George Zogopoulous 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution We have developed novel transgenic mouse models of Palb2 gene in pancreatic cancer.
Collaborator Contribution Dr Zogopoulous' team has identified patients with PALB2 germline mutations with pancreatic cancer. This collaboration will provide us with human tissues in this unique subgroup of patients for further analyses.
Impact Ongoing work
Start Year 2016
 
Description Collaboration with Dr Go Van Dam 
Organisation University Medical Center Gronigen
Country Netherlands 
Sector Hospitals 
PI Contribution Collaboratively submitted a Stand Up to Cancer Dream Team grant (Dutch Cancer Society - American Association of Cancer Research). Title of grant submitted: Optical guided perSonalized Pancreatic dUctal adenocaRcinoma treatment (SPUR)
Collaborator Contribution Collaboratively submitted a Stand Up to Cancer Dream Team grant (Dutch Cancer Society - American Association of Cancer Research). Title of grant submitted: Optical guided perSonalized Pancreatic dUctal adenocaRcinoma treatment (SPUR)
Impact Awaiting outcome of grant application
Start Year 2013
 
Description Collaboration with Dr Marc Tischkowitz 
Organisation University of Cambridge
Department Department of Medical Genetics
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of transgenic mouse models of pancreatic cancer based on impaired fanconi anaemia genes.
Collaborator Contribution Collaborative discussion based on Dr Tischkowitz's previous work on fanconi anaemia genes in pancreatic cancer.
Impact Multiple discussions including the use of biological specimens from Dr Tischkowitz's collaborators in Canada.
Start Year 2012
 
Description Collaboration with Dr Marketa Janatova 
Organisation Charles University
Department First Faculty of Medicine
Country Czech Republic 
Sector Academic/University 
PI Contribution Analyses of PALB2-mutant pancreatic cancer patients.
Collaborator Contribution Dr Janatova has the largest series of pancreatic cancer patients with inherited PALB2 gene mutation.
Impact Work currently in progress. Output will be anticipated in 12 months.
Start Year 2016
 
Description Collaboration with Dr Talia Golan 
Organisation Sheba Medical Centre
Department Institute of Oncology
Country Israel 
Sector Hospitals 
PI Contribution Analyses of PALB2-mutant pancreatic cancer patients.
Collaborator Contribution Dr Golan has identified pancreatic cancer patient/s with inherited PALB2 gene mutation in Israel.
Impact Work currently in progress. Output will be anticipated in 12 months.
Start Year 2016
 
Description Collaboration with Dr Thomas Roddy (Agios Inc., Boston, USA) 
Organisation Agios Pharmaceuticals
PI Contribution We have provided tumour cell lines generated from pancreatic cancers derived from DNA-repair deficient mouse models of pancreatic cancer.
Collaborator Contribution The team at Agios will collaborate to identify specific metabolomic features of DNA-repair deficient pancreatic cancer to identify novel biomarkers and therapeutic targets.
Impact Agios has provided data on metabolomic analyses. This collaboration is multi-disciplinary, involving biochemists, laboratory research (molecular oncology) and clinicians.
Start Year 2017
 
Description Collaboration with Dr Timo Ten Hagen 
Organisation Erasmus University Medical Center
Department Department of Experimental Surgical Oncology
Country Netherlands 
Sector Academic/University 
PI Contribution Development of imaging-based transgenic mouse model of pancreatic cancer.
Collaborator Contribution Training and expert advice on the use of window chambers in mouse models of pancreatic cancer.
Impact This included a collaborative visit to Dr Ten Hagen's laboratory in Erasmus Medical Centre.
Start Year 2011
 
Description Collaboration with Prof Edward Whang 
Organisation Brigham and Women's Hospital
Department Department of Surgery
Country United States 
Sector Hospitals 
PI Contribution Analysis of biomarkers and status of signaling pathways in pancreatic cancer tissues.
Collaborator Contribution Provision of human pancreatic cancer tissue microarray with associated clinical outcome data.
Impact Ongoing work.
Start Year 2012
 
Description Collaboration with Prof Steven Gallinger 
Organisation Mount Sinai Hospital (Canada)
Department Samuel Lunenfeld Research Institute
Country Canada 
Sector Hospitals 
PI Contribution Development of transgenic mouse model of pancreatic cancer.
Collaborator Contribution The use of biological samples (i.e. DNA and tumour specimens) as part of the Ontario Pancreatic Cancer Study.
Impact Development of a collaborative project involving the sequencing of pancreatic cancer specimens to identify somatic mutations involved in disease progression.
Start Year 2012
 
Description Collaboration with Professor Stefan Boeck 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Country Germany 
Sector Academic/University 
PI Contribution Analyses of PALB2-mutant pancreatic cancer patient.
Collaborator Contribution Prof Boeck has identified pancreatic cancer patient with inherited PALB2 gene mutation in Germany.
Impact Work currently in progress. Output will be anticipated in 12 months.
Start Year 2016
 
Description Production of Cambridge Cancer Centre Early Detection Infographics 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Input into the production of Early Cancer Detection Infographics to give physical scientists an overview of the development, progression and current standard of care for pancreatic cancer. This will help to identify areas where there may be opportunities for research to aid early detection of pancreatic cancer.
Year(s) Of Engagement Activity 2016,2017