When I started to write this blog I wondered what scientific article to discuss and my first thought was my PhD thesis! Being the only child studying biology, my family finds it difficult to fathom the philosophical side of my basic life science research. La PhD memoir is dedicated to my family and friends – hope this gives you an idea of what I was up to for 6 years!
My PhD dissertation was to study the role of macrophages in the breast tumor micro-environment. Sounds Latin already? Now let’s simplify this. Think about our body to be a well-planned city. A city is divided into well-defined sectors with its unique zipcode; each sector branches into roads and streets and every building has a documented postal address. Just like a city, our body is extremely well-organized too; every cell has a defined postal address. Tumor is like an illegal building that springs up, but its façade is so deceiving that it is difficult to differentiate this illegal construction from the legal ones. Our body, just like a city council has ways to demolish illegal structures. These include a battalion of immune cells, one particular kind are macrophages. When this contingent of macrophages along with other immune cells arrives to clear tumor, they are duped to actually reinforce the tumor! This reinforcement is essential for tumor because without the city’s facilities tumor growth cannot be sustained. During my PhD I studied this paradox – how does tumor hijack the adjacent environment, in particular macrophages, to bolster its growth.
To add another dimension of complexity, a tumor also has the same DNA, a.k.a., building material, as the adjoining structures. Even the defense system in our body has the same genetic makeup. One of the gene readers is a protein called Ets2. When I started with my PhD thesis, previous studies showed that Ets2 was more important in the adjacent environment rather than in tumor cells to assist in tumor growth. As I have mentioned earlier, environment consists of adjacent normal cells as well as immune cell contingent, I wanted to methodically study the role of Ets2 in the macrophage compartment. One way to do this would be to delete Ets2 only in macrophages while not affecting Ets2 in all other cell-types of the body. Imagine our body as a BMW plant manufacturing 1, 3,5,6,7 series, a.k.a., cell types. Now if 3 series are macrophages and Ets2 steering wheel, then in this BMW plant only 3 series would have a missing steering wheel whereas 1, 5, 6 and 7 series will all carry an intact steering wheel.
To tweak cancer environment at such high resolution, mice represent a powerful model. Mice are an ideal system for cancer studies because they are physiologically similar to humans and can be manipulated genetically to study diseases at high resolution. That said, it took 2 years of my Grad School life to start getting tumor-bearing mice that had no Ets2 in macrophages – yes, mouse genetics has its own time course! It was well-worth the wait though, since I discovered that Ets2 in macrophages did not affect the primary tumor but boosted metastasis. Consider metastasis a local mafia gang in Palo Alto and some gang members branching out to Fremont, Sacramento and Los Angeles. Ets2 is the device that is required to make this gang powerful in distant places like Los Angeles, but does not affect its power at its original place in Palo Alto. The next 4 years of my Grad School life was to figure out the mechanism. Is Ets2 important when some gang members leave Palo Alto, or is it important when they are travelling to Los Angeles or is Ets2 the reckoning force when the members arrive at Los Angeles or when they establish their power in Los Angeles? It gets complicated, but that’s what makes it challenging, right? I figured that Ets2 is important at the very last step when tumor aggressively grows at metastatic site, or simply out, when gang established power in Los Angeles!
To give you a more visual sense of Ets2-macrophage-breast cancer story, see the image below. Hope it makes sense now!
