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Using data from more than 100,000 malignant and non-malignant cells from 15 human brain metastases, researchers at UCSF revealed two functional prototypes of metastatic cells from seven different types of brain tumors, each containing immune and non-immune cell types
.
Their findings, published Feb.
17 in the journal Cell, provide a potential roadmap for metastatic tumor formation that could be used to design therapies to improve the treatment of metastatic patients
.
Researchers at UCSF, led by first author Hugo Gonzalez, PhD, senior author Jeroen Roose, PhD, and the late Zena Werb, PhD, analyzed metastatic tumor cells (mtc) and identified metastatic tumor cells (mtc) in seven metastatic brain cancers.
Eight functional processes of mtc expression were identified
.
They found that these specialized and complementary processes work together within a single cell to form two recurrent cellular archetypes, inflammatory cells and proliferating cells, that coexist in every metastatic tumor, caused by shaped by immune cells
Brain metastases are the most common type of brain cancer and are nearly 10 times more common than brain cancers
.
While treatments for brain metastases have improved in recent years, much remains to be learned about how metastases develop
The team combined high-dimensional single-cell analysis and experimental models of human brain tissue metastases from different cancer types to identify and understand recurrence patterns during the formation of metastases in patients
.
They also identified a similar metastatic microenvironment, as well as an immunosuppressive stroma rich in T cells and metastasis-associated macrophages, that appear to play a role in the dynamics of both archetypes
"These archetypes coexist in every metastatic tumor," Gonzalez said.
"For mtc that don't proliferate, these cells are reprogrammed to express genes for inflammation, stress, and other changing conditions
.
It's likely that these tumor-immune interactions are shaping the the state of the stromal cells
Inspiration from renowned cancer researchers
"Zena Werb was the first to see the potential and feasibility of collecting human metastases and combining it with cutting-edge technologies such as single-cell transcriptomics and cytology," Gonzalez said.
"By analyzing human metastases,
she believes, Metastases in the brain, we can determine the relationship between these MTC-organized cellular processes and their specific microenvironment
.
"
Werb is a world-renowned researcher in cancer biology and associate director of the UCSF Comprehensive Cancer Center
.
She transformed the field by emphasizing the critical role of a cell's local "neighborhood" in determining tumor growth and behavior
"From the beginning, she believed in the project and encouraged me to stick with it, even though it was very difficult to collect and process these rare small samples," Gonzalez said
.
Roose added that Gonzalez's work provided an important foundation for the team's collaboration with the UCSF Endeavor project, which aims to better understand how metastasis occurs when cancer cells interact with host cells surrounding a tumor
.
Roose found it very rewarding to see Hugo complete the final stages of the brain transfer project
.
"I could see Zena walk into my office, give us a thumbs up and give us a big hug
article title
Cellular architecture of human brain metastases
