HSCI researchers develop organoids to model cancer and test potential treatments

 

Lung cancer, the leading cancer killer in the U.S., is often missed in its earlier stages. And while recent imaging advances offer earlier detection, early-stage lung cancers still have no targeted treatments.

But that could change. HSCI researchers at Boston Children’s Hospital, in collaboration with scientists at Boston University and UCLA, have created a platform that can accelerate the identification and testing of potential treatments: “organoids” developed from lung cells.

Led by Carla Kim, Ph.D., HSCI Executive Committee member and Cancer Program co-leader, the researchers developed these “miniature lungs” to track a common type of hard-to-treat lung tumor from its origins. Studying adenocarcinoma initiated by mutations in the KRAS gene, the team captured the molecular changes that took place as the tumor progressed. They reported their findings in the journal Cell Stem Cell.

Modeling early lung cancer

The researchers studied several models of early lung cancer: tumor samples from patients with early lung cancer, genetically engineered mouse models, and lung organoids. They derived the organoids either from mouse lung stem cells, or from lung cells created from human induced pluripotent stem cells.

“We know very little about the early events that transform a normal lung epithelial cell into a cancer cell,” said Kim, who was a co-senior author of the study along with Jane Yanagawa, M.D., of UCLA and Darrell Kotton, M.D., of the Boston University School of Medicine. “Here, we were able to use early-stage samples from lung cancer patients to show that our organoids truly mimic what happens in patients at the very early stages. We can see changes in the organoids within seven days that can take months to see in mice and even longer, probably years, in patients.”

Tracking lung cancer as it develops

The researchers introduced the cancer-initiating KRAS mutation into the lung organoids’ alveolar progenitor cells. They then used single-cell RNA sequencing to see what genes were expressed and when.

Over time, they saw decreased expression of genes marking mature lung alveolar cells. Meanwhile, expression of genes involved in early lung development — markers of cancer progression — increased.

Encouragingly, studies in mice and in patient tumor samples mirrored the organoid findings.

“These studies lay a groundwork for finding new therapeutic avenues for early-stage lung cancer,” said Kim. “Currently, KRAS-mutant tumors are usually resistant to therapy by the time they are diagnosed.”

Testing potential treatments

Although this study focused on KRAS-driven lung cancer, the researchers believe their organoid approach could facilitate studying other kinds of cancer, as well as testing candidate drugs.

“The collaborating teams really made progress together in understanding a stage of lung cancer that has been very tough to study in humans,” said Kotton. “We hope these new human and lung organoid models of early lung cancer formation will now serve as powerful drug development platforms.”

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This story was originally published on the Boston Children’s Hospital website on September 4, 2020, under the title “Lung ‘organoids’ capture early-stage lung cancer; could help test treatments.”

Source article: Dost, A. F. M., Moye, A. L. et al. (2020). Organoids Model Transcriptional Hallmarks of Oncogenic KRAS Activation in Lung Epithelial Progenitor Cells. Cell Stem Cell. DOI: 10.1016/j.stem.2020.07.022

Supporters of the study include Boehringer Ingelheim Fonds, the National Institutes of Health (R01 HL090136, R01 HL132266, R01 HL125821, U01 HL100402 RFA-HL-09-004, R35HL150876-01, R24HL123828, U01TR001810, R01HL128172, R01HL095993, R01HL122442, U01HL134745, and U01HL134766), the Damon Runyon Cancer Research Foundation (DRG:2368-19), the Burroughs Wellcome Fund, Hope Funds for Cancer Research, an IASLC Young Investigator Fellowship, the American Cancer Society (RSG-08-082-01-MGO), the V Foundation for Cancer Research, the Thoracic Foundation, the Ellison Foundation, the American Lung Association (LCD-619492), the Harvard Stem Cell Institute, and the Lung Cancer Initiative at Johnson & Johnson.