Postdoc Feature Series with Marie Parsons

Our latest installment in the Postdoc Features series promoting the research and lives of our impressive postdocs and postdoc alumni. 

Heidi Meyer & the Postdoc Association.

Marie Parsons

Recent Achievements:

• 2019 Hunter Cancer Research Alliance- Future Leaders Group conference travel bridging scheme
• 2018 Hunter Cancer Research Alliance- Career Advancement Fellowship in Cancer Research
• 2018 Hunter Cancer Research Alliance, Future Leaders Group- Best Paper, Biomarkers and Targeted Therapies

Recent Publications:

• Parsons, M. J., Tammela, T., & Dow, L. E. (2021). WNT as a driver and dependency in cancer. Cancer Discovery.
• Zafra, M. P., Parsons, M. J., Kim, J., Alonso-Curbelo, D., Goswami, S., Schatoff, E. M., ... & Dow, L. E. (2020). An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants. Cancer Discovery, 10(11), 1654-1671.
• Sakthianandeswaren, A.*, Parsons, M. J.*, Mouradov, D.*, MacKinnon, R. N., Catimel, B., Liu, S., ... & Sieber, O. M. (2018). MACROD2 haploinsufficiency impairs catalytic activity of PARP1 and promotes chromosome instability and growth of intestinal tumors. Cancer discovery, 8(8), 988-1005. *denotes equal authorship

Where are you from in Australia and what was it like to move to New York?

I grew up in Newcastle, which is just north of Sydney. It's a city, but it's also a beach town, so literally the opposite to New York. It’s more like a California vibe and California climate. I went to grad school in Melbourne, which is a lot more similar to New York in some accounts. It's been hard adjusting to the cold weather in New York but it’s also super exciting. I've seen snow before – we do get snow in Australia and I've been fortunate enough to travel – but I've never been in an actual snowstorm. It's been really fun to leave the lab a little early and wander through Central park.

What is your favorite thing about New York City?

The opportunities. There are so many things to do and activities to participate in - it's almost overwhelming. You have that opportunity to do anything you want or be anything you want. And then all the culture – the museums and Broadway (when it was open). I like having the choice of all these different things to do. Back home where I grew up, we only had a tiny Art Gallery, the ballet would come to town once a year, and concerts – if you're lucky they might stop by after they've gone to Sydney which is obviously going to be a much bigger crowd. So, I like having the opportunity to do so many things in New York. I also love Central Park and that you can get out of the city and go upstate. There are just so many options.

As a runner, what are your favorite routes in the city?

I think my favorite places to run are Central Park or the West Side Highway along the piers. Central Park has it all. I never get sick of it and still pinch myself sometimes that I can run there as much as I please when I and many others have travelled half way across the world just to visit. I also love running by the water which reminds me of home. I was running a lot pre-Covid, around 50-55 miles per week, but that came to a halt during Covid so I’ve been trying to get back into it again. I’ve run two marathons previously and I was trying to do the 9+1 to get to do the marathon this year. That hasn’t happened because of Covid, but I’d like to try again for next year. I’d also love to start a running club – I tried to start one with my lab, and recruited one rotation student, but still actively looking for others to join. 

What is your favorite pizza topping?

Hawaiian. Since moving to New York, I’ve learned that this is very controversial, but I think pineapple has a place on pizza. Back home, we have a lot of pizza restaurant chains, and at these restaurants they'll have the various pizza options, and Hawaiian is always on there. Here, it's down at the bottom and you can't buy it as a single slice. 

What is your favorite thing about being a postdoc?

That’s kind of a hard one! It’s exciting, but it’s also scary. I would say you are very confident when you finish grad school, you’ve defended your thesis, you consider yourself an expert and have developed a set of skills your chosen field. But you’re also very supported as a grad student and no one is going to let you fall too far. In my own experience, I had a postdoc mentor and a PI, so someone was holding my hand inside and outside of the lab. In contrast, as a postdoc, there is finally the opportunity to see what you’re made of and to see if you can take what you’ve learned and apply it. I think that's probably the most rewarding, but also the most challenging part. As a postdoc, you're not necessarily employed for one particular skill, but how you can apply what you've learned and you’re ability to pick up new things. One of the most exciting parts of being a postdoc is having the freedom to learn new things and having the chance to figure them out on your own. Often in grad school, your PI will play a huge role in your project, maybe even micromanaging and always wanting to know what you are up to. But as a postdoc, it's really up to you to drive your project and also how much you share with your PI. There will be some external motivation when it's needed, but it's up to you to pick what you find is interesting and run with it. Of course, along with that freedom of choice, it’s equally scary because you can be following loose ends for days or months even, and sometimes you have to follow multiple different paths and narrow it down to what works out the best. Intimidating, but definitely exciting to have control over deciding what you want to follow up.

How do you like living in postdoc housing on Roosevelt Island?

I don't mind living on Roosevelt Island, it's quiet which can be nice after being in Manhattan. I’m at the southern end, so I step out of my apartment and there's immediately the Cornell Tech hills and the east river which is really nice. I’m in the Cornell Tech housing which is new and furnished and this is really great for new postdocs because it helps make the transition to a new city, or even country, really easy. So, for postdocs like me who arrived from overseas, I was able to settle in very quickly and jump straight in life and work in NYC. I think that’s a big Pro. On the other hand, there aren’t many food options on the Island and it is very quiet so you can’t be as spontaneous as you could be in Manhattan and transport into the city can be unreliable on the weekends. In saying that, it’s a great spot for families and it is really beautiful in the spring in cherry blossom season and summer. If I had to move I think I’d move to the upper east side or the west side either by Central Park or downtown in Tribecca – somewhere where I could drop my bags off and go running and not have to run from work, then come back to work to pick things up. Most of the running clubs don’t have any storage. You ‘come as you are’ and start running, because they start in Central Park and so no one is there to mind your bags if you leave them.

What led you to become a cancer biologist?

Originally, in college, I wanted to be a physiotherapist, because I did a lot of sports and I liked science and human physiology. Instead, I got into my section choice program, biomedical science, but now I feel like it was meant to be. For the biomed degree, you take classes in a bit of everything – from basic human physiology, to neuroscience, to genetics, to oncology, to immunology, etc. That was really good because I realized I was most intrigued by genetics. In Australia, before you're allowed to enter grad school, you have to do an “Honors Year”, which is a research-intensive year, kind of like a mini-Masters. You propose your project, do a written proposal and an oral proposal, and then you're allowed one year to do the work. At the end you write and are graded on a mini thesis. When I was thinking about my honors year, I was really interested in genetics, and the lab that had the best fit was studying colon cancer. I wouldn't have said until that point that I was really interested in colon cancer, but I liked oncology, and I like genetics, so it seemed like a sensible choice. After that, I really liked the area of study and felt there was so much more to learn, plus the idea of making a difference in this field really excited me! In Australia it's very common to continue your PhD in the same lab that you do your Honors Year in. I would have been happy to do this – my lab was in my hometown and right by the beach, it was the kind of place where work life balance is key and you would easily find people at the beach after 4pm on a nice day. But my supervisor left just over half way through my time in the lab to become a patent attorney. So, I was motivated to broaden my search and I discovered some labs in Melbourne that were doing more complicated genetics work with a large focus on colon cancer. It was here my passion to work in colorectal cancer flourished, I found myself in one of Australia’s leading medical research institutes, surrounded by so many incredible scientists and felt really inspired to pursue a career in medical research and specifically to make a difference in the lives of colorectal cancer patients.

 As for my postdoc, my current boss is actually Australian and by total coincidence I met him at a conference where I was presenting my work. This conference was by the beach and it mostly consists of three major research institutes and a stellar lineup of international guests, so you usually know most people. I was really curious about him. It was probably the most engaging poster session I’d ever given – he asked me really good questions and kind of triggered what I had already been thinking of as far as my research. About a year later, at the AACR (American Association of Cancer Research) conference in Washington DC, our paths crossed again and I asked to interview for a postdoc position in his lab. This was early into my third year of grad school, so actually a bit early to be applying for jobs. But it worked out, because about three months after I finished my thesis he contacted me saying I had a position and here I am.

What project are you working on right now?

My major focus in the lab at the moment is trying to characterize genetic variants of a gene in colorectal cancer called KRAS. KRAS is mutated in around 40% of colorectal cancer (CRC). Outside of CRC, KRAS is the most frequently mutated oncogene, highlighting its importance as a driver of tumorigenesis. Research has traditionally focused on KRAS as a single mutation and many studies have used one sole mutation known as KRAS-G12D to model all mutations in cancer. In recent years, we have discovered the genetic complexity of KRAS mutations in cancer and discovered that there is a spectrum of mutations in KRAS. These distinct alleles not only have unique effects on KRAS activation but they show tissue specificity across cancer subtypes which is really interesting. So for example, in the colon cancer the most frequent mutations are G12D, G12V, G13D and G12C and in the normal colon (just looking at Kras mutations) these very subtle differences in KRAS dramatically alters the intestinal epithlium causing widespread hyperplasia within colon crypts. Thus, the premise of my project is to investigate the role of these distinct mutations in the context of colon cancer with the aim of discovering what biological changes these mutations drive to promote tumor growth and how we can exploit these unique differences to develop targeted therapies.

 Two specific examples I’m working on are how KRAS-G12C and G13D mutants drive CRC progression and how to treat each of these specific mutations in CRC. At the moment, RAS-driven CRC patients don’t receive personalized treatment – they’ll get a stock standard chemotherapy regime, they’re excluded from treatments using EGFR antibodies, which work in other cancers, due to a lack of benefit or emergence of resistance. The KRAS mutation has generally been considered undruggable until very recently. It’s just in the last few years that it’s been shown in retrospective studies that some colon cancer patients with the KRASG13D mutation do actually benefit from EGFR inhibitors, but the same drug doesn’t work with other KRAS mutation variants. There’s also another drug, AMG510, which is the first specific inhibitor of KRAS12C. Part of my work is aimed towards teasing out what the mechanism is by which these drugs can inhibit mutated KRAS. I will look in a tumor setting and see if using a combination of drugs to target different aspects of the pathway may reveal any synergy in combining therapies to reduce tumor burden.

What techniques do you use?

I use a mix of mice and organoids. We have a few different approaches to modeling CRC including genetic models that express genes solely in the colon and distal small intestine. This has been a big shift in our field, because a lot of people just model in the small intestine, and while similar, it’s not the same. One of my other projects is to try and build more flexible, faster, and genetically complex models of CRC by using viral delivery of base editors to induce specific mutations or organoid transplantation into the colon. It's great because you can deliver it postnatally. In a lot of genetic models, the genes are switched on from when the mice breed and are always active versus a postnatal delivery. With tumor mice, you're limited to “at the moment” experiments. I think my mice get sick around 16 or 20 weeks. So, you have that short timeframe where you have to A) wait for them to develop anything and detect the cancer – we use an endoscopy suite to check. Then, B) you can deliver drugs, but if you want to deliver drugs pre tumor development, then you really have to catch these mice quite early and changes can be happening before you see a full tumor. If this model works, it'd be a really nice model to test whether drugs will stop tumor initiation or have any effects in those early stages. I'm hopeful I’ll be able to test it pretty soon, or at least have an idea of the tools within that work. I also work a lot with organoids to model specific mutations and to test out drugs before going in vivo. Colon organoids are surprisingly more difficult to make than small intestinal organoids. Once we have an organoid, the next step is to test the efficacy and find the mechanism for various drugs. Most of the drug testing work I have been doing actually uses organoids, then in the long term we can transplant these organoids into the colons of mice and test drugs in vivo.

What are your future career goals?

My first dream goal would be to get a PI position back in Australia. My ultimate goal is to improve the outcome for CRC patients through developing advanced preclinical models that further our knowledge of CRC biology and improve translation of discoveries from the lab to the clinic.

Following my postdoctoral training in the US, I plan to return to Australia to deploy the platforms and models I will have developed and establish an independent research group. There are certain institutions that I think foster good research community, especially for young PIs, so that would be ideal. Surprisingly, there are not a lot of labs studying CRC in Australia which is interesting considering Australia retains the highest incidence and mortality rate in the world. So, my dream job would be to have a mouse modeling lab where I can use the models that I've developed here to establish my own group in Australia. Part of the reason I joined the Dow lab is because of the expertise in mouse modeling and gene editing technologies.