Cancerous tumors grow when cancer cells replicate, diversify and spread, a process usually attributed to cancer stem cells. Until now, studies of tumor growth in PDAC focused mainly on cancer stem cells instead of the surrounding tissue including non-cancerous cells in the microenvironment. Previous studies investigated tumor growth in PDAC by visualizing specific, previously known markers for cancer stem cells to follow their behavior. However, these methods did not consider the contribution of other, marker-negative cells to tumor growth. A new study published in the prominent journal Cell Reports from the Center for Experimental and Molecular Medicine at Cancer Center Amsterdam and Oncode Institute reveals for the first time how cells in PDAC can acquire cancer stem cell properties following cues from their microenvironment.
Marker-free tracking
To understand the role of all cancer cells in a PDAC tumor, the research team used a technique known as marker-free lineage tracing which they had previously developed and applied in other cancer models. “The elegance of this method is the independence of a specific marker, allowing the growth dynamics of all tumor cells to be revealed,” says lead author Sophie Lodestijn, a PhD student in the laboratories of Maarten Bijlsma and Louis Vermeulen. Lodestijn and her co-workers combined their novel results with mathematical models to explain the dynamics of cancer growth in PDAC. The results surprised them.
Location, location, location
The team found that the microenvironment of a tumor can influence cell behavior. The tumor microenvironment is the ecosystem surrounding a tumor cell and includes non-cancerous cells, the extracellular matrix and blood vessels. Notably, it was found that any PDAC cancer cell can develop stem cell functionality depending on their proximity to certain structural cells called stromal fibroblasts. “The ability to contribute to tumor growth is not a cell-intrinsic feature as previously assumed, but instead is instructed by cues from the microenvironment,” says Sophie Lodestijn. More specifically, “we found that cancer cells that were located close to stromal fibroblasts harbored high stem cell functionality as measured by clonal outgrowth. This means that the microenvironment is dominant in driving tumor growth.” As a result, therapies targeting cancer stem cells are likely to fail because other cancer cells will simply replace them when the microenvironment is right. These results suggest that future therapies for PDAC should focus on changing the stromal niche microenvironment to discourage development of stem cell characteristics in PDAC cells.
Image of labeled (red) daughter cells derived from one parental cell in pancreatic cancer tissue (cell nuclei in blue). In our study we used these pictures to obtain expansion size data in combination with mathematical modelling to analyze tumor growth of established pancreatic cancer tumors.
For more information, contact corresponding authors: m.f.bijlsma@amsterdamumc.nlor l.vermeulen@amsterdamumc.nl.
This work is supported by the Academic Medical Center (Amsterdam), The New York Stem Cell Foundation and grants from the Dutch Cancer Society, the Maurits en Anna de Kock Stichting, Worldwide Cancer Research, the Maag Lever Darm Stichting, the European Research Council, and ZonMw.
[researchers from Cancer Center Amsterdam] Sophie C. Lodestijn, Daniël M. Miedema, Kristiaan J. Lenos, Lisanne E. Nijman, Saskia C. Belt, Khalid El Makrini, Maria C. Lecca, Cynthia Waasdorp, Tom van den Bosch, Maarten F. Bijlsma & Louis Vermeulen.