Staff Profile

Current Position:

          Newcastle University Research Fellow at Newcastle University Cancer Centre, Biosciences Institute, Newcastle University.

Previous positions:

            Postdoctoral Fellow : MRC Human Genetics Unit, IGMM, Edinburgh University, UK.

            Postdoctoral Fellow : The Roslin Institute, Edinburgh University, UK.

            Postdoctoral Fellow :  INSERM U1052, Lyon, France.

            Postdoctoral Fellow : International Agency for Research on Cancer, Lyon, France. 

Qualifications :

           Fellow of the Higher Education Academy, UK.

           Ph D : National Center for Cell Science, Pune, India. 

           Masters in Biotechnology : Devi Ahilya University, Indore, India.

           Bachelor of Science (Hons. in Microbiology) : Delhi University, India.

Research Interest: Understanding the factors and mechanisms affecting genetic instability and epigenetic remodelling in the context of hepatocellular carcinoma (HCC) 

Summary: HCC is the sixth most common type of cancer and the second most frequent cause of cancer-related deaths worldwide. Over 70% of patients have incurable disease at presentation, due to late detection.  The combination of rising incidence and lack of treatments has contributed to marked increases in HCC mortality – which is predicted to continue increasing for the next 20 years. Hence, much clinical research is focused on developing novel more effective therapeutic options for these patients. It is widely recognized that to have a major impact on survival, early detection and better treatment strategies are urgently required. Hence my focus is the identification of novel therapeutic target(s) and diagnostic and treatment stratification biomarkers for HCC patients.

The main focus of the lab is to identify and characterise epigenetically deregulated therapeutic targets, primarily L1 autonomous retrotransposons. Also, we are exploring DNA methylation patterns in HCC samples to identify potential Synthetic Lethal genes and evaluate them as novel therapeutic targets for HCC. Activation of retrotransposons has been well documented in cancers of different origins leading to an increase in genetic instability by promoting gene deletions/duplications and genomic rearrangements. Active retrotransposons can influence gene expression patterns, generate truncated or antisense gene transcripts and alter splicing patterns [1, 2]. I have demonstrated that active retrotransposition is associated with activation of oncogenic pathways in hepatocellular carcinoma (HCC) [3,4]. However, the mechanism/factors leading to activation of retrotransposons during cancer development are unclear. Hence the research questions we are addressing are: the relationship between the activation of L1s and HCC status and the mechanism (s) of retrotransposons activation in the context of HCC.

In parallel, we are aiming to identify diagnostic, prognostic and treatment stratification biomarkers by focusing on gene expression changes and DNA methylation in peripheral immune cells and circulating cell-free DNA and RNA to develop 'liquid biopsy tools'. The ultimate aim is to develop potential therapeutic strategies and biomarkers for HCC patients in order to reduce lethality associated with the disease.

Collaborators: 

Newcastle University: Prof Helen Reeves, Prof John Lunec, Dr Gordon Strathdee, Liver Fibrosis Unit and Shoba Amarnath

Outside Newcastle: Prof Richard Meehan, MRC Human Genetics Unit, IGMM, Edinburgh University.

                                  Dr Jose L. Garcia-Perez, MRC Human Genetics Unit, IGMM, Edinburgh University.

                                  Prof Gerald G. Schuman, Paul-Ehrlich-Institute, Germany.

                                  Dr Jamila Faivre, U1193 INSERM, University Paris-Sud, France. 

                                  Dr Geoff Faulkner, Mater Research Institute, Brisbane, Australia.

Funding secured:

• Sep 2022-Aug 2025: Alice Stephenson Bequest Fund PhD studentship as co-PI (Laboratory/Scientific development Lead). ‘Identification of ‘liquid biopsy’ predictictive biomarkers in patients with advanced hepatocellular carcinoma’.
• Oct 2021-Sep 2024: MRC DiMEN iCASE PhD studentship as CoI (Laboratory/Scientific development Lead). ‘Liver Cancer – Developing DNA-PK as a predictive biomarker and clinical target’.
• Aug 2020-Jan 2022: JGW Patterson Foundation Pump Priming Award Grant as PI.  ‘LINE1 and TGFβ axis in hepatocellular carcinoma’.
• Jan 2018: International PhD Studentship from the Government of Thailand as PI. ‘Analysis of DNA methylation patterns in Hepatocellular Carcinoma to identify novel therapeutic targets and biomarkers that predict response to therapy’.
• Dec 2017-Dec 2019: JGW Patterson Foundation Special Research Grant as PI.   ‘Understanding factors involved in regulation of Long-Interspersed-Nuclear-Elements (LINE1) retrotransposons in context of hepatocellular carcinoma’.
• Sep 2017: Newcastle University Overseas Research Scholarship for a PhD Student.  ‘Understanding factors involved in regulation of Long-Interspersed-Nuclear-Elements retrotransposons in context of Hepatocellular Carcinoma’.
• Feb 2016-July 2022: Newcastle University Research Fellowship

Full list of publications can be found at Google scholar profile: https://scholar.google.co.uk/citations?user=TuX5z44AAAAJ&hl=en

References:

1. Kazazian HH, Jr.: Mobile elements: drivers of genome evolution. Science 2004, 303(5664):1626-1632.

2. Ayarpadikannan S, Kim HS: The impact of transposable elements in genome evolution and genetic instability and their implications in various diseases. Genomics & informatics 2014, 12(3):98-104.

3. Shukla R, Upton KR, Munoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T, Brennan PM, Baillie JK, Collino A, Ghisletti S et al: Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 2013, 153(1):101-111.

4. Schauer SN^†, Carreira PE^†, Shukla R^†, Gerhardt DJ, Gerdes P, Sanchez-Luque FJ, Ghisletti S, Faivre J, Ewing AD, Richardson SR, and Faulkner GJ: L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. Genome Research 2018, 28(5):639-653. (^† These authors contributed equally).

Undergraduate Teaching

Supervision of research projects of undergraduate students in Biomedical Sciences

Lectures

• Genetics and Human Disease UG course Stage 3 (BMS3010) – ‘Epigenetics’.

• Genetics module (BGM1004) since 2019.
• Cell biology module (CMB1004) since 2020.

Postgraduate Teaching

Supervision of the Faculty of Medical Sciences MRes and MPharm students

Lectures

• MRes Genetic Medicine Module (MMB8030) – ‘Epigenetics’.
• MRes-Cell Signalling-Module: Therapeutic Applications of Cell Signalling Pathways (MMB 8050) – ‘Repeat elements in health and disease’.

Ph. D Students

Bassier Zadran:  Role of retrotransposons in hepatocellular carcinoma origin and progression – potential biomarker and therapeutic target? Passed Nov 2021

Praveen D Sudhindhar: Understanding factors involved in regulation of Long-Interspersed-Nuclear-Elements retrotransposons in the context of Hepatocellular Carcinoma. Passed Mar 2022

Chalermsin Permtermsin: Jan 2018 – July 2022:  Analysis of DNA methylation patterns in Hepatocellular Carcinoma to identify novel therapeutic targets and biomarkers that predict response to therapy. Currently in the writing up phase

Fanni Palinkas: Sep 2021 - Jan 2021: ‘Liver Cancer – Developing DNA-PK as a predictive biomarker and clinical target’ 

Other teaching related activities

·   Markings: UG Stage 1 essay setting and marking; MRes and UG dissertations, oral presentations, abstracts; MBBS Stage I and II assignments, mini-reviews and patient leaflets.

·       Ph. D assessment panels

·       Tutor within School of Biomedical, Nutritional and Sport Sciences, Newcastle University.

·       Ph. D external examination for the University of Edinburgh.

• Eldafashi N, Darlay R, Shukla R, McCain MV, Watson R, Liu YL, McStraw N, Fathy M, Fawzy MA, Zaki MYW, Daly AK, Mauricio JP, Burt AD, Haugk B, Cordell HJ, Bianco C, Dufour J-F, Valenti L, Anstee QM, Reeves HL. A pdcd1 role in the genetic predisposition to nafld-hcc?. Cancers 2021, 13(6), 1412.
• Sudhindar PD, Wainwright D, Saha S, Howarth R, McCain M, Bury Y, Saha SS, McPherson S, Reeves H, Patel AH, Faulkner GJ, Lunec J, Shukla R. Hcv activates somatic l1 retrotransposition—a potential hepatocarcinogenesis pathway. Cancers 2021, 13(20), 5079.
• Zaki MYW, Mahdi AK, Patman GL, Whitehead A, Mauricio JP, McCain MV, Televantou D, Abou-Beih S, Ramon-Gil E, Watson R, Cox C, Leslie J, Wilson C, Govaere O, Lunec J, Mann DA, Nakjang S, Oakley F, Shukla R, Anstee QM, Tiniakos D, Reeves HL. Key features of the environment promoting liver cancer in the absence of cirrhosis. Scientific Reports 2021, 11(1), 16727.
• Shukla R, Mjoseng HK, Thomson JP, Kling S, Sproul D, Dunican DS, Ramsahoye B, Wongtawan T, Treindl F, Templin MF, Adams IR, Pennings S, Meehan RR. Activation of transcription factor circuity in 2i-induced ground state pluripotency is independent of repressive global epigenetic landscapes. Nucleic Acids Research 2020, 48(14), 7748-7766.
• Shukla R, Reeves HL, McPherson S, McCain M, Sudhindar P, Bury Y, Faulkner G, Lunec G. Hepatitis C virus infection, endogenous retrotransposons activation and cancer risk. Journal of Hepatology 2020, 73, S401–S652.
• McLaughlin K, Flyamer IM, Thomson JP, Mjoseng HK, Shukla R, Williamson I, Grimes GR, Illingworth RS, Adams IR, Pennings S, Meehan RR, Bickmore WA. DNA Methylation Directs Polycomb-Dependent 3D Genome Re-organization in Naive Pluripotency. Cell Reports 2019, 29(7), 1974-1985.e6.
• Schauer SN, Carreira PE, Shukla R, Gerhardt DJ, Gerdes P, Sanchez-Luque FJ, Nicoli P, Kindlova M, Ghisletti S, Santos AD, Rapoud D, Samuel D, Faivre J, Ewing AD, Richardson SR, Faulkner GJ. L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis. Genome Research 2018, 28(5), 639-653.
• Ravà M, D'Andrea A, Doni M, Kress TR, Ostuni R, Bianchi V, Morelli MJ, Collino A, Ghisletti S, Nicoli P, Recordati C, Iascone M, Sonzogni A, D'Antiga L, Shukla R, Faulkner GJ, Natoli G, Campaner S, Amati B. Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18. Hepatology 2017, 65(5), 1708-1719.
• Shukla R. Retrotransposons and genetic instability in hepatocellular carcinoma. Hepatic Oncology 2017, 4(1), 5-8.
• Klawitter S, Fuchs NV, Upton KR, Muñoz-Lopez M, Shukla R, Wang J, Garcia-Canadas M, Lopez-Ruiz C, Gerhardt DJ, Sebe A, Grabundzija I, Merkert S, Bock A, Held U, Witthuhn A, Haase A, Sarkadi B, Löwer J, Wolvetang EJ, Martin U, Ivics Z, Izsvák Z, Garcia-Perez JL, Faulkner GJ, Schumann GG. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nature Communications 2016, 7, 10286.
• Thomson JP, Fawkes A, Ottaviano R, Hunter JM, Shukla R, Mjoseng HK, Clark R, Coutts A, Murphy L, Meehan RR. DNA immunoprecipitation semiconductor sequencing (DIP-SC-seq) as a rapid method to generate genome wide epigenetic signatures. Scientific Reports 2015, 5, 9778.