A Surprising New Cell of Origin for Lung Cancer

July 31, 2023 — by John Knox, Knox Communications

If you can imagine the entire population of Fresno, California wiped out, then you can understand what it means to say that more than half a million people will die in the U.S this year from lung cancer. It’s the leading cause of cancer death in this country, and one of the world’s leading fatal diseases.

But Tushar Desai, MD, MPH, professor of pulmonary, allergy & critical care medicine and investigator in the Institute for Stem Cell Biology and Regenerative Medicine, is working at the cellular level to lower those numbers. His work involves AT1 cells and AT2 stem cells, the two cell types that line the gas exchange region of the lung, where extremely deadly forms of cancer known as adenocarcinomas form.

Desai and colleagues had previously shown that AT2 stem cells generate conventional (and lethal) lung adenocarcinomas. Now they have identified the AT1 cell as another cell of origin for lung adenocarcinoma. This is surprising because AT1 cells are not stem cells and were not previously considered capable of generating cancer.

AT1-derived tumor cells closely resemble conventional adenocarcinoma tumor cells that originate from AT2 stem cells, but there is a major difference between the two: AT1 cells are much less aggressive and repeat the pattern of a slower growing form of human lung adenocarcinoma called lepidic cancer. An article appearing in the July 19, 2023 issue of Nature, expands on their findings.

One of the key factors thought to drive lung adenocarcinoma growth is Wnt signaling, which is an important pathwayregulating stem cells and believed to promote lung adenocarcinoma growth. Desai and colleagues activated Wnt signaling in AT2-derived tumors and saw the tumors become more aggressive as expected. But when Wnt signaling was activated in AT1-derived tumors, it unexpectedly had an anti-tumor effect.

“Tumors derived from type 1 cells appear to have a paradoxical response to Wnt,” Desai says.

He explains that this finding has important implications for guiding personalized cancer treatment. That’s because while blocking Wnt could help some patients, it could also harm others, depending on the cellular origin of the tumor. Desai considers this to be one of the key takeaways from their research, namely that knowing the cell of origin may be critical for devising the proper treatment regimen for each patient.

“Personalized medicine in cancer care has been very successful, currently based on how the tumor looks under the microscope, stage of disease spread, and identity of which genetic mutation drives the disease. However, our results suggest that incorporating the cell of origin could further refine precision medicine in cancer to achieve even better outcomes,” Desai says.

Furthermore, Desai and colleagues discovered a new and unexpected role for KRASG12D, a common genetic mutation that drives lung, intestinal, and pancreatic cancers: The mutation is not just involved in making a cell divide, but it is also able to convert an ordinary lung cell back into a stem cell. If this is also the case in other tissues, it could similarly result in cancers arising from non-stem cells that masquerade as stem cell-derived, with patients unwittingly receiving anti-cancer treatments that do more harm than good.

In follow-up research, Desai is collaborating with the labs of fellow Stanford physicians Max Diehn, MD, PhD, and Joseph Shrager, MD. Together, they are working to see if these findings hold true for human lung adenocarcinoma. These studies involve performing complex profiling of patient lung cancer cells from lepidic and conventional adenocarcinoma, which should also yield a wealth of new information that stimulates new avenues of research for working towards a cure.

Desai is a member of the Stanford Cancer Institute and a principal investigator of Ludwig Cancer Research, which funded this research.