Hijacked Cell Signals May Trigger Most Common Lung Cancer

Lung cancer research has primarily focused on how mutations in a person's genes may signal cells to become more vulnerable to malignancies or even resistant to treatment. This robust area of study is critical to understanding the biology of cancer and improving patient care.

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But today, lung cancer research is moving beyond the genes of origin and focusing instead on its cellular beginnings. "It is not so much the mutation, but which cells get the mutation that seems to matter," says Douglas Brownfield, PhD, of Stanford University. His lab and others identified the most prominent cells of origin for adenocarcinoma, the most common form of non-small cell lung cancer. The key cells are found in the air sacs of lungs and called alveolar type 2 (AT2) cells.

"We have focused over time on the right genes and right cell types, now we need to follow the right cellular processes to really get a handle on what's going on in the case of lung adenocarcinoma," says Brownfield, who is now conducting such research with the help of an American Cancer Society grant.

What are AT2 Cells?

The lungs contain tiny air sacs called alveoli. These grape-like clusters contain two main types of cells:

  • Alveolar type 1 (AT1) cells are long and thin and allow oxygen to enter and carbon dioxide to exit. This vital process of gas exchange is what facilitates your ability to take a breath.
  • Alveolar type 2 (AT2) cells are cube-shaped structures that secrete a liquid substance (called surfactant) that prevent the air sacs from collapsing so you can keep breathing.

But AT2 cells have a unique feature: They function as stem cells in the adult lung. When alveoli cells are damaged, AT2 cells either self-renew or reinvent themselves as type 1 cells. Brownfield's team found that a cell-signaling pathway called Egfr/K-RAS plays a role in AT2 cell self-renewal. Many of the genetic mutations involved in the development of adenocarcinoma occur in this KRAS pathway. He believes that lung adenocarcinoma occurs when the normal KRAS signaling is somehow hijacked, causing AT2 cells to continuously self-renew without ever reinventing themselves as the other critical AT1 cells.

"Hyperproliferation [accelerated growth and division] of type 2 cells basically fill the alveoli. Normally you'd have an air sac with one or two AT2 cells strategically placed in corners, but when they proliferate, they aren't respecting those boundaries anymore and form this large aggregated mass, which disrupts gas exchange and promotes airway collapse," Brownfield explains.

The Whole Genome in Single-Cell Resolution

The goal of Brownfield's Society-funded research is to determine exactly how AT2 cells regenerate, and use that information to identify new ways of diagnosing the transformed cells at earlier stages of lung cancer. Such understanding could one day help scientists develop new targeted treatments for the disease.

In previous research, he introduced a KRAS mutation into mice and found that AT2 were specifically sensitive to it. "When we gave the same mutation to all other alveolar cells, they were either unable to generate adenocarcinomas or, if they did, it was much more rare or not as pronounced as when we introduced the mutation in type 2 cells specifically," he says.

3D projection of adult mouse lung cells

(Image: 3D projection of adult mouse lung. Alveolar type 2 (AT2) cells are in green. AT1 and all other cells are red.)

Now, instead of introducing the cancer mutation, he plans to knock out the KRAS gene from AT2 cells in mice to see what happens in the normal lung. "When we delete these genes in type 2 cells, will they be unable to act as stem cells, or lose their ability to duplicate or to give rise to type 1 cells?" he asks.

To do this, he is using an emerging technique called single cell expression profiling. The novel method provides him a look at individual cell subtleties that can go undetected using older molecular analysis tools.

"It allows you to see the entire genome in single cell resolution. You can see subsets of type 2 cells. This hasn't been possible before," explains Brownfield. "We haven't been able to see these subtle differences. And there are differences. This new approach has really opened the door for my work."

A Blueprint of Blueprints

Understanding how genes and cells work together in the body or are mutated will help lung cancer researchers build "better and smarter methods of earlier disease detection and treatment," Brownfield says.

"The genome is a blueprint of blueprints," he says. "As cell types get specified, a sub blueprint is opened. Being able to have a pin on the cell origin will be able to clear a lot of the noise out, molecularly speaking, as to what is actually going on."

But it's not just as simple as studying the disease system. Brownfield likens his cellular research to car manufacturing and repair.

"We built cars. When a car breaks, we can look at how we built it and how to fix it. We didn't build ourselves," says Brownfield. "We don't even now really understand how our body tissues are built and put together both at the cellular and molecular levels. So what we are doing now is kind of reverse engineering a black box, or maybe a grey one."

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