EACR Travel Fellowships are co-sponsored by Worldwide Cancer Research and provide funds up to €3,000 to early-career cancer researchers. For more information on how to apply for Travel Fellowships, you can visit the EACR website.
Home institute and country: JSS College of Pharmacy, Karnataka, India
Host institute and country: CECAD Research Center, University of Cologne, Germany
Dates of visit: 01 May 2018 – 01 July 2018
My current research work is focused on understanding the role of hypoxic microenvironment in cancer progression, therapy resistance and poor patient prognosis, which represents an emerging focus in cancer biology. Under such a stressful microenvironment, it is reported that cancer cells evolve to survive and progress by developing adaptive mechanisms such as endoplasmic reticulum stress-response, autophagy and Nrf2-dependent antioxidative responses, which are cytoprotective. Hypoxia-inducible factor 1α (HIF-1α) is identified as a critical factor that stimulates cytoprotective-adaptive mechanisms by transcriptionally upregulating genes that are responsible for angiogenesis, altered glucose metabolism (Warburg effect) and cell proliferation. In this process I have collaborated with Dr. Nirmal Robinson, with support from the EACR.
Below: The joy of doing science, PowerPoint presentation sent by Sandhya Chipurupalli
How did you hear about EACR Travel Fellowships?
I came across the EACR while I was looking to get membership in scientific organisations related to research in the cancer field. As soon as I learned about the EACR through web sources, I applied for membership. After 3 months of the membership, I was notified by the EACR team about the travel fellowships offered. At the same time I was invited by Dr. Nirmal Robinson to work in his laboratory at CECAD Research Center, University of Cologne, Germany.
Why did you choose the host lab?
In most cancers, it is shown that hypoxia plays an important role in tumor cell adaptation to low energy availability, which promotes tumour growth and increased resistance to therapy. In this context, our findings showed that hypoxic stress drives certain survival strategies, such as enhanced autophagy and Nrf2-dependent antioxidative responses as a mechanism cellular adaptation to such hostile microenvironments, causing in cancer cell progression. In contrast to these findings, we came across the findings of Dr. Nirmal Robinson and his team, who have a long-standing interest in understanding the cellular stress pathways that provide protection to the cells under pathological conditions, such as infection and cancer. Their work revealed that pathogens inhibit autophagy and Nrf2-dependent anti-oxidative responses (ARE), thus inducing cell death. Interestingly, their work also corroborates with our findings that HIF-1α is transiently up-regulated upon pathogen-induced stress. Together, their findings and investigations in our lab suggest that understanding the stress responsive pathways targeted by the pathogen could provide pharmacological targets to prevent complex pathologies, such as cancer, and we could benefit from the lessons learned from cancer cells in protecting immune cells to fight against invading pathogens. This made us choose Dr. Robinson’s laboratory.
I hereby express my sincere thanks to the EACR team for recognising my potential and encouraging me.
Can you summarise the research you did on your visit?
I have studied the significance of HIF1α in regulating autophagy and Nrf2-dependent antioxidative responses. I did the knockdown HIF-1a in MCF-7 cells using established protocols in Dr. Robinson’s lab. Following gene silencing, I examined cell proliferation using JuLi Br Live Cell Analyser; investigated autophagy by immunoblotting for LC3; autophagic flux by transfecting cells with a plasmid expressing GFP-DSRed-LC3 followed by flowcytometric analysis. To examine if HIF-1α regulates Nrf2-dependent antioxidative responses, we studied the expression (Western blotting) and localisation of Nrf2 (confocal microscopy). We also quantified the mRNA of Nrf2-dependent anti-oxidative response genes by qRT-PCR. Similarly, we infected cells depleted of HIF-1α with S.Typhimurium, analysed autophagy and Nrf-2 dependent response as detailed above. We have also validated the identified small molecules in regulating HIF-1α and its dependent adaptive mechanisms by treating MCF-7 cells with 3 selected small molecules.
What was a personal highlight of your trip?
During my visit, I was fortunate to meet Prof. Greg Goodall, Head of the Gene regulation section, Centre for Cancer Biology, University of South Australia, Adelaide, Australia. He is an eminent scientist working to understand the role of miRNAs in epithelial to mesenchymal transition (EMT) through which cancer cells become metastatic and invasive. My interaction with Prof. Greg gave novel insights to improvise my research work further. We are also planning a collaboration with his lab at the Centre for Cancer Biology, University of South Australia.
Did you have a personal mentor or anyone who particularly helped you?
My mentor Dr. Robinson and his team Dr. Julia Fischer, Dr. Raja Ganesan, Dr. Rajeev Ranjan, Chiara Calabrese, Jennifer Klimek, Nina Hos were very helpful in all ways. Among all, Dr. Raja Ganesan is the senior post doc in the lab and he was the person with whom I worked closely with and he was great help. He taught me all the techniques of transfection in adherent cells with siRNA, immunoflourescent staining and infecting cells with bacteria.
Have you brought back any specific knowledge that has benefited your home lab?
I learnt the technique of gene silencing in adherent cells using small interfering RNA and the technique of live cell imaging to study proliferation using Evos FL Auto 2 microscope. I have discussed these techniques with all the people at my home institution and we are trying to establish these techniques in our home lab.
How has this visit been beneficial to your research and your career?
My short-term visit to Dr. Robinson’s lab has fulfilled my research objectives and in addition, it has opened a few more interesting and intriguing questions to explore in my area of research. I would take up those research questions as a challenge and proceed further to explore the mysterious mechanisms underlying the HIF-1a dependent stress responses in cancer cells leading to therapy resistance.
Is there anything else you’d like to mention?
I highly appreciate the support rendered by the EACR from their travel fellowship award as this helped me to cope with my financial stress and to carry out meaningful research. This award was very encouraging and has built my confidence and is an additional credit to my career. I hereby express my sincere thanks to the EACR team for recognising my potential and encouraging me. I look forward to work towards the best research.