Undergrads 2024

Glioblastoma (GBM) is the most frequent and aggressive primary malignant brain tumour. Despite rigorous therapeutic efforts, the prognosis of GBM remains extremely low, with a median survival of approximately 14 months after diagnosis. Our lab studies a cyclin-like protein called Spy1 which has been found to be elevated in GBM. Spy1 overrides cell-cycle checkpoints and avoids conditions that would normally cause cell cycle arrest, leading to increased and uncontrolled cell proliferation. Our research has demonstrated Spy1’s involvement in regulating senescence, a prolonged state of cell cycle arrest, specifically within the context of GBM. We have shown that targeting Spy1 leads to an increase in the number of senescent cells, and importantly, these senescent populations can be effectively eliminated using senolytics, drugs that can target and eliminate senescent cells.  

I joined the Porter Lab at the beginning of my first year of university as an outstanding scholar. I started as a lab volunteer and a junior student in the Peer Mentor Network (PMN) where I learned the basics of cancer research from more experienced students. Over time, I took on a more active role, identifying knowledge gaps, assisting with experiments, and collaborating with peers to address current research challenges. Working on my own project in my upper years allowed me to develop my critical thinking and problem-solving skills, and taught me the benefits of working in a collaborative environment. This experience has ignited a passion within me for research and lifelong learning, and I am truly grateful to have had the opportunity to pursue research under the guidance of Dr. Porter and the research associates. 

My project looked at the functional consequences of Tuberin mutations, more specifically the A614D and C696Y missense mutations. Mutations in this protein result in a disease called Tuberous Sclerosis Complex (TSC). TSC causes benign tumour formation in various organs of the body including the brain, heart, eyes, and lungs among others. These point mutations result in Tuberin losing its regulatory function over protein synthesis and mitotic onset. I investigated the punctate perinuclear localization pattern that is seen with these point mutations by looking at the lysosome as a potential cause for this. We hypothesize that Tuberin mislocalization to the lysosome results in a loss of Tuberin’s regulatory role over mitotic onset. I also aimed to develop cells that express these Tuberin mutations at physiological levels so we can better understand the interactions of these Tuberin mutants at endogenous levels.

I joined Porter lab in my 4th year of undergrad to do a thesis and my experience in the lab was great, being able to work in the lab allowed me to gain valuable skills in not only critical thinking and problem solving but also oral and written communication, every member of the lab was very kind and generous with their guidance. The skills that I developed in the lab will be extremely beneficial in the future and I want to thank everyone in the lab for their continued support throughout the year.

My project aimed to illuminate the role of the protein Spy1 in genomic instability and drug resistance in Glioblastoma. Investigating how Spy1 deregulates DNA damage checkpoints and increases treatment resistance can help us validate Spy1 as a potential therapeutic target and improve future treatment for Glioblastoma. 
 
Being in Porter Lab was an incredible experience. I learned a lot about dedication, resilience and overcoming failure, though I must also credit my success to the help of my supervisor Dorota, my mentor Hema, and the rest of the lab for their assistance and kindness. In the future, I plan to continue in a career in the health sciences.
The cell cycle is a highly regulated process consisting of cyclins, CDKs, and checkpoints that control cellular progression. p53, a tumor suppressor protein is activated in the presence of DNA damage, halting the cell cycle, thereby allowing DNA repair to occur prior to cell division. Tuberin (TSC2), another tumor suppressor protein, regulates the G2/M transition and negatively regulates mammalian target of rapamycin complex 1 (mTORC1) by binding to the GTPase activating protein (GAP) domain, effectively suppressing protein synthesis and cell growth. Previously, our lab has shown that Tuberin regulates mitotic onset by retaining Cyclin B1 (the G2/M cyclin) in the cytoplasm depending on nutrient availability. Due to this unique ability, and Tuberin’s ability to sense nutrient status in the cell, we aim to investigate whether Tuberin could be playing a role in DNA damage response by delaying the onset of mitosis and allowing for DNA repair mechanisms to occur. My project focused on creating Tuberin-null U2OS cell lines using CRISPR-Cas9 editing technology. Tuberin-ΔGAP lines were also constructed to clarify whether Tuberin’s role at arrest is independent of mTORC1 activity. To induce DNA damage, etoposide, a topoisomerase II drug was used, and cells were analyzed by flow cytometry using DAPI staining to determine cell cycle profiles. This project will provide further insight into the role of Tuberin at mitotic onset and elucidate the mechanisms of DNA damage induced carcinogenesis, TSC, and other cancers. 
 
“My time in the Porter Lab has truly been one of the most pivotal experiences of undergraduate years. I joined the lab in my second year where my first exposure to the lab’s research was through the Peer Mentor Network. I was blown away by the amazing projects being investigated in the lab and honestly, found the work to be quite daunting. I then began my own project in third year, actively conducting experiments and engaging in research. Despite the challenges and hours of troubleshooting, I can confidently say that this experience has been instrumental in shaping my academic and personal growth. Not only have I gained a multitude of technical skills, but I have also honed my critical thinking, problem solving, and resilience. This journey has been truly gratifying, from the realization that my hands had become steady while pipetting, to finally imaging a successful western blot. Most importantly, the level of mentorship I have received throughout my thesis is unparalleled. I would be lost without the support, advice, and patience of the many grad students in our lab. Their guidance made such a supportive learning environment and helped me gain confidence in my own abilities as a researcher. I am also sincerely grateful to Dr. Lisa Porter and Dr. Elizabeth Fidalgo da Silva for all the opportunities for growth, and I wish all the best to the next group of thesis undergrads!” 

My project focuses on tool development and neuroendocrine prostate cancer. A standard treatment protocol for castrate-resistant prostate cancer involves the use of androgen receptor inhibition therapies. While effective, in some cases, androgen deprivation through treatment can pressure prostate cancer cells to differentiate into neuroendocrine prostate cancer cells (NEPC). Current treatment options for NEPC remain limited, and understanding the molecular mechanisms guiding this differentiation will be essential in developing future therapies. My research questions focuses on whether we can stop the cells from transforming into such an aggressive form of NEPC cells by using Cyclin-dependent kinase (CDK) inhibitors. I use LNCaP cell lines and the zebrafish animal model to test the hypothesis that elevated levels of Cyclin A and/or Cyclin B1 support the evolution to NEPC and that select targeting of their kinases, Cdk1 and/or Cdk2, at the G2M checkpoint, could represent an effective therapy for preventing progression and treating NEPC. Furthermore, I constructed fluorescent splitFAST vectors that allow real-time monitoring of the interaction between Cyclin B1 and Tuberin. Our lab has observed that Tuberin expression plays a role in embryonic neurodifferentiation and could be a potential player within NEPC differentiation. The fluorescent vectors allow us to visualize the effects of the CDK inhibitor. While research is constantly testing the unknown, there is strong rationale and data to support that this is a promising direction that could dramatically impact overall outcomes on a global scale.

I joined Porter Lab and my third year and it has been one of the most fulfilling experiences in my university career so far. I’m incredibly thankful to Dr. Porter and Ras, especially Dr. Elizabeth Fidalgo de Silva for supporting me and helping me in my journey as a scientist. I’m incredibly grateful for the Porter Lab community for supporting and being a great team. My time in Porter Lab has taught me invaluable skills that I am looking forward to carry on with me into my next steps for my science career.

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