Ashwini Nagaraj’s doctoral thesis highlights the importance of stratifying cancer according to etiology-related phenotypes
Ashwini Nagaraj’s thesis entitled "Unravelling Lung Cancer Heterogeneity and Associated Therapeutic Responses Using In Vivo and Ex Vivo Model Systems” focuses on investigating the role of tumor cell of origin in establishing lung cancer phenotypic and functional heterogeneity using genetically engineered lung cancer mouse models. Her doctoral dissertation was publicly examined on 7 December.
Lung cancer is known to be both genetically and histologically heterogenous disease. Despite progress in the development of treatments against lung cancer, there are no targeted therapies for patients with certain common lung cancer driver mutation such as KRAS or LKB1. Due to the poor prognosis of the patients lung cancer still remains to be the major cause of cancer-related deaths worldwide.
Even though genetic alterations drive the development of cancer, multiple other factors are known to influence the heterogeneity of the established tumors and thus contribute to therapy response. In her thesis, “Unravelling Lung Cancer Heterogeneity and Associated Therapeutic Responses Using In Vivo and Ex Vivo Model Systems”, M.Sc. Ashwini Nagaraj has focused on investigating the role of tumor cell of origin in establishing lung cancer phenotypic and functional heterogeneity using genetically engineered lung cancer mouse models.
Ashwini has done her thesis work at FIMM in the group of FIMM-EMBL Group Leader Emmy Verschuren. The thesis has been co-supervised by Dr. Denis Kainov. Her doctoral dissertation was publicly examined 7 December 2018, with the permission of the Faculty of Medicine of the University of Helsinki.
Mouse models expand our knowledge on tumor heterogeneity
Ashwini graduated from the Bangalore University, India, in 2007, majoring in biochemistry. After graduating, she worked as a Junior Research Fellow at Indian Institute of Science (IISc) studying immunomodulatory effects of Japanese Encephalitis Virus. In 2011 she joined FIMM as a CIMO-Research Fellow to work on a collaborative project between Denis Kainov and Emmy Verschuren and the next year, she started her PhD project in Emmy’s group.
Her thesis consists of three articles and one manuscript currently being under review. All utilise a mouse model harboring conditional expression of Kras driver mutation together with loss of a tumor suppressor gene Lkb1 or p53. Some of the key findings of Ashwini’s thesis have also been validated in clinical patient material.
The results of the thesis demonstrate that the tumor cell of origin is crucial in determining survival, lung cancer subtype, and associated immune microenvironment in the mouse model used. In addition, signaling downstream of Kras was shown to be stratified according to tumor histotype, rather than genotype.
My thesis work highlights that beyond understanding lung cancer at the genetic level, investigation of histotype-specific etiology, and spatially distributed functions including oncogenic signaling activities is important for designing effective therapies.
- Ashwini Nagaraj
As an important part of her thesis work, Ashwini has investigated the utility of tumor tissue slices and tumor-derived primary cell cultures for functional diagnostics.
She showed that tumor tissues slices from freshly resected mouse lung tumors are useful models for short-term treatment studies and that optimization for slice thickness is important to retain maximum viability of the slices. Establishment of murine NSCLC cell culture models was shown to be challenging but possible using a conditional reprogramming protocol.
In the last part of her thesis work, Ashwini investigated the predictive power of cell culture models by performing short-term treatment with combination of drugs targeting oncogenic signaling pathways.
I am currently assessing the long-term effect of combined signaling pathway inhibition in in vivo models. I am very much looking forward to know the outcome of my experiment, and how it compares to related clinical trial results that study response in lung cancer patients!
Ashwini is very pleased with the collaborative and interdisciplinary research environment at FIMM. She is proud of her good communication skills and feels that efficient communication is essential for the successful completion of big collaborative projects. As a mother of 3.5 years old daughter, her ability to combine family life with completing the thesis project must also be admired.
Ashwini will spend some more time at FIMM to finish her experiments. Her future plans are not yet settled but she is considering to switch the focus of her work from animal models to more clinically oriented studies.
M.Sc. Ashwini Nagaraj defended her doctoral dissertation entitled: "Unravelling Lung Cancer Heterogeneity and Associated Therapeutic Responses Using In Vivo and Ex Vivo Model Systems" on 7 December. Associate Professor David Dankort, McGill University, Québec, Canada served as the opponent and professor Jaakko Kaprio as the custos.