E72a Mobile tissues: Lung

Topic

The lung combines two physical and biological characteristics that, together, make it especially prone to developing aggressive, rapidly growing tumors: high exposure to mutations and a rich blood supply.

The first characteristic is that lung tissue is continuously exposed to carcinogens found in tobacco smoke; this significantly increases the mutation rate in lung cells and causes lung tumors to accumulate—over time—a much higher total mutational burden than tumors in organs less exposed to external carcinogens.

The second characteristic is the lung's rich vascularization—a dense network of blood vessels—which facilitates rapid tumor growth to a much larger size before growth plateaus, and also enables tumor cells to spread to other parts of the body much earlier than in tissues with poorer blood supply.

Furthermore, lung tissue lacks uniform density, combining regions of varying density; this creates significant spatial variations in oxygen diffusion within the tumor itself, resulting in zones that are better oxygenated than others depending on the density of the surrounding tissue. Added to this is the fact that the patient's breathing movements constantly shift the tumor and surrounding tissues, effectively altering the position of the tumor's invasive front with every breath.

Most lung carcinomas are of the non-small-cell type—including subtypes such as adenocarcinoma and squamous cell carcinoma—and are often driven by specific driver mutations in genes that control tumor cell growth. When one of these driver mutations is present, it is possible to treat the patient with an inhibitor drug specifically targeting that mutation; the drug's efficacy depends on the concentration required to inhibit half of the tumor cells—the lower the concentration needed to achieve this inhibition, the more effective the drug is at eradicating the tumor cell clone carrying that driver mutation.

The simulator for this type of lung tumor can replicate both the tumor's initial response to the inhibitor drug and the subsequent emergence of resistance to that same drug by varying the tumor cells' mutation rate under the selective pressure exerted by the drug itself: the higher the mutation rate, the sooner clones of tumor cells with additional mutations—which no longer respond to the inhibitor drug—appear within the tumor, in a process of clonal evolution driven by treatment pressure.

It is this combination—a high mutation rate due to tobacco exposure, rich vascularization that accelerates growth and spread, irregular oxygenation caused by tissue heterogeneity, and an invasive front that shifts with the patient's breathing—that makes the lung tumor a particularly complex case to model, and explains why, even when an effective inhibitor drug exists for a specific driver mutation, resistance to that drug tends to develop over time.

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