A team of researchers at the Johns Hopkins Kimmel Cancer Center’s Sol Goldman Pancreatic Cancer Research Center has created a 3D genomic profiling method to detect tiny precancerous lesions in the pancreas known as pancreatic intraepithelial neoplasias (PanINs). These PanINs are responsible for one of the most aggressive and fatal forms of pancreatic cancer.On May 1, an article published in Nature presented the most comprehensive 3D map of precancerous lesions in the human pancreas, which could potentially lead to early detection of pancreatic ductal adenocarcinoma (PDAC) and other forms of pancreatic cancer in the future.
According to Laura Wood, M.D., Ph.D., an associate professor of pathology and oncology at the Kimmel Cancer Center and the Johns Hopkins University School of Medicine, the discovery of a high number of precancerous lesions, or PanINs, in the normal regions of the pancreas was unexpected. This study sheds light on the prevalence of these precancerous lesions in the pancreas and underscores the need for further research and understanding in this area.
Researchers have discovered a type of pre-cancerous lesion in the pancreas called pancreatic intraepithelial neoplasia (PanIN), which could potentially lead to a better understanding of how pancreatic cancer develops.
Co-led by Alicia Braxton, D.V.M., Ph.D., a postdoctoral fellow at the Johns Hopkins University School of Medicine, and Ashley Kiemen, Ph.D., an assistant professor of pathology at the medical school, the study sheds light on the early stages of pancreatic cancer.
Due to their small size, PanINs are difficult to detect and cannot be identified through standard radiology exams. This poses a challenge in diagnosing pancreatic cancer at an early stage, often leading to advanced metastasized cancer by the time it is discovered in patients.
The current methods of 2D histological staining, where tissue is thinly sliced, stained, and observed under a microscope, offer a limited understanding of PanINs, which leaves researchers in the dark about their origins and their role in cancer development. In order to gain a better understanding of PanINs, the researchers have developed a 3D approach.
By thinly slicing and staining tissue from 38 normal pancreatic samples into hundreds of sequential 2D slides, the researchers utilized a machine-learning pipeline called CODA to analyze and reconstruct the slide images into digital 3D images.
The 3D reconstructions provided a detailed view of the complex structure of PanINs.The study found that there are networks of connected PanINs in the pancreas, with an average of 13 PanINs per cubic centimeter. The range of PanINs per cubic centimeter varied from 1 to 31. Patients with PDAC in other parts of the pancreas appeared to have a higher PanIN burden compared to those with nonductal disease, although the difference was not statistically significant.
Additionally, the researchers examined eight samples through 3D-guided microdissection and DNA sequencing of specific PanINs. Genomic analysis showed that the networks consisted of genetically distinct PanINs, each driven by different gene mutations, including mutations in the cancer-causing gene Kirsten rat sarcoma.The KRAS virus, commonly found in most pancreatic cancers, has been discovered. According to Wood, the presence of multiple precancerous lesions due to independent mutations has not been observed in other organs. However, this discovery of PanINs will allow for targeting them, particularly through KRAS. CODA is not currently usable for diagnosis, but one of its advantages is its applicability to any tissue, disease, or model organism, according to Kiemen. She also expressed that this discovery is just the beginning, and further investigation is needed to understand its implications for other organ tissues.Pancreatic intraepithelial neoplasias (PanINs) are a key focus when it comes to understanding the early stages of pancreatic cancer. Dr. Christopher Wood, one of the study’s authors, emphasizes the importance of identifying which PanINs are clinically relevant to the disease, in order to advance cancer prevention efforts. The team believes that creating detailed anatomical and molecular maps of PanINs is crucial, as it will provide a better understanding of the disease’s early precursors. By examining these precursors in 3D, researchers hope to gain insights that may have been previously overlooked. In addition to Dr. Wood, the study’s co-authors include Mia Grahn, André Forjaz, Jeeun Parksong, Jaanvi Mahesh Babu, Jiaying Lai, Lily Zheng, Noushin Niknafs, Rebecca Reichel, Sarah Graham, Alexander Damanakis, Catherine Fischer, Stephanie Mou, and Cam.eron Metz, Julie Granger, Xiao-Ding Liu, Niklas Bachmann, Yutong Zhu, YunZhou Liu, Cristina Almagro-Pérez, Ann Chenyu Jiang, Jeonghyun Yoo, Bridgette Kim, Scott Du, Eli Foster, Jocelyn Hsu, Paula Andreu Rivera, Linda Chu, Fengze Liu, Elliot Fishman, Alan Yuille, Nicholas Roberts, Elizabeth Thompson, Robert Scharpf, Rachel Karchin, Ralph Hruban, Pei-Hsun Wu, and Denis Wirtz of Johns Hopkins.
Other authors were from the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and the Institute of Cancer Research at the Henan Academy of Innovations in Medical Science in ZhengzhouThe research was funded by grants from the National Cancer Institute at the National Institutes of Health, the Sol Goldman Pancreatic Cancer Research Center, Lustgarten Foundation, Break Through Cancer, the Buffone Family Gastrointestinal Cancer Research Fund, the Allegheny Health Network – Johns Hopkins Cancer Research Fund, the American Association for Cancer Research (AACR)-Bristol Myers Squibb Midcareer Female Investigator Grant, the Rolfe Pancreatic Cancer Foundation, the Joseph C. Monastra Foundation for Pancreatic Cancer Research, and the Gerald O Mann Charitable Foundation (trustees Harriet and Allan Wulfstat), S.Wojcicki and D. Troper received the Lustgarten Foundation-AACR Career Development Award for Pancreatic Cancer Research (in honor of Ruth Bader Ginsburg) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-067 and 2021-1-I2M-018).
Kiemen, Hruban, Wu, Wirtz and Wood applied for a patent on June 24, 2022, for the 3D genomic profiling technique. This patent is managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
