Abstract
Whether tumors arising from tubular tissues grow outward or inward depends on the size of the malignant duct involved, a finding that could help clinicians better define the aggressiveness of certain cancers.
Cancers that arise from tubular tissues can, like belly buttons, be innies or outies. A new imaging technique, backed by computer models, shows that the direction of tumor expansion depends on the size of the duct involved, a finding that could help clinicians assess the aggressiveness of cancers of the pancreas, lung, liver, and other organs with cylindrical internal structures.
“It is a new description of how tumors form,” says Joshua Reineke, PhD, of South Dakota State University in Brookings, who was not involved in the research. “There is the potential that it will have a clinical impact, and it's certainly something that researchers in this area should be aware of as they develop new treatment strategies, diagnostics, and models.”
This image, which shows cancer growing inside the pancreatic duct of a mouse, was obtained using a new technique to study 3-D tissue samples. It reveals that cancers can begin as endophytic tumors that grow into the ducts (above) or exophytic tumors that grow outward.
The study began as an exploration of what pancreatic ductal adenocarcinomas look like in 3-D (Nature 2019;566:126–30). On flat-plane histology slides, the tumors appear highly heterogeneous, with few features indicative of particular subtypes. Perhaps, thought Axel Behrens, PhD, of the Francis Crick Institute (FCI) in London, UK, 3-D imaging might offer a better window into the cancer's cellular organization.
Behrens and his colleagues first developed an immunostaining method called fast light-microscopic analysis of antibody-stained whole organs—FLASH—which, through careful sample preparation, preserves the geometric complexity of the pancreas and can reveal the organ's intricate architecture down to a single cell.
Applying this protocol to mice engineered to develop pancreatic tumors, the researchers observed two types of lesions: endophytic ones that grew into the ducts and exophytic ones that grew outward into the surrounding parenchyma. The direction of tumor growth didn't depend on specific oncogenic driver mutations; what mattered was epithelial geometry.
The researchers showed that cancer cells, regardless of their localization in the ductal tree, lost their one-sided patterning of tension-generating cytoskeletal proteins, altering the elasticity of transformed cells in a way expected to bend the epithelium inward.
Behrens's FCI colleague Guillaume Salbreux, PhD, then led an effort to model the impact of those biophysical changes on ductal structure. Their simulations revealed that one variable determined whether tumors would grow in or out: ductal diameter. Above 17 μm, the lesions formed inward; below that threshold, the high curvature of the duct prevented inward growth and lesions developed outward.
This was what Behrens's team saw when they validated the model in murine and human pancreatic tumors. “We could confirm that prediction literally to the micrometer,” Behrens says. “This is a totally fundamental physical principle.”
The researchers observed the same phenomenon in mouse tumors in lung and liver ducts, indicating that local curvature of the tissue, combined with mechanical changes within the transformed cells, guides the direction of cancer morphogenesis.
“It's astonishingly simple,” says Jonathan Celli, PhD, of the University of Massachusetts, Boston—and the results are “convincing,” he adds. “The imaging is absolutely beautiful, and the rich insight it gives you into the heterogeneity of these ductal networks is really impressive.”
Behrens and his colleagues validated the mouse findings in only a handful of patient samples, but their analysis indicated that outward-growing lesions tend to display a more invasive phenotype than inward-growing ones. This could mean that patients with exophytic lesions might have poorer treatment responses and survival outcomes, although that remains to be proven, he acknowledges.
Notably, he adds, some features of 3-D tumor directionality often correlate with pathologists' measurements in two dimensions, so it might be trivial to incorporate a directionality biomarker into a routine diagnostic workup. “There is clinical potential,” Behrens says. “I hope this will aid going ahead with future patients' stratification.” –Elie Dolgin
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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