Miguel Bronchud on pancreatic intraepithelial neoplasias
Miguel Bronchud, Co-Founder and Advisory Board at Regenerative Medicine Solutions, shared on LinkedIn:
“Why don’t we all die from pancreatic cancer?
Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them extremely difficult to study.
Painstakingly, several researchers at Johns Hopkins University School of Medicine, (Baltimore, MD, USA) have been able to provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution.
To elucidate genetic relationships between and within PanINs, they developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing.
From these samples, authors calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic K-RAShotspot mutations.
They found that most PanINs originate as independent clones with distinct somatic mutation profiles.
Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins.
Interesting finding- especially for those of us who have insisted over four decades (La Patogenia del Cancer, 1978 – Biblioteca Nacional de Madrid) that cancer pathogenesis cannot be “only genetics”, or strictly mono clonal.
Instead, in origins “field epigenetic” and dependent upon differentiation molecular dysfunctions, and different microenvironmental factors (leading to immune escape).
In summary, 3D genomic mapping reveals multifocality of human pancreatic precancers. Adult pancreatic tissue contains hundreds of precancerous lesions, which can develop into cancer in a small proportion of people.
In 46 samples of healthy pancreatic tissue, researchers identified multiple lesions with cancer-triggering KRAS-gene mutations.
“This high burden is particularly striking considering the relatively low incidence of pancreatic cancer, suggesting that individual [lesions] have extremely low risks of progression,” write the researchers at John Hopkins University.
Exciting findings also because the pancreas has double embryonic origins and function (endocrine and exocrine).”
Source: Miguel Bronchud/LinkedIn