Numerous ‘clues’ can be obtained from the tumor microenvironment to understand how the disease is evolving: an Israeli study presented during the last congress of the American Association for Cancer Research (https://www.aacr.org/) has shown that cancer-associated fibroblasts (or CAFs) change during breast cancer development and progression and that these changes are associated with differences in clinical outcome.
CAFs have significant heterogeneity and plasticity in the tumor microenvironment, and they also secrete a considerable variety of factors that contribute to regulating tumor occurrence, development, metastasis and even therapeutic resistance. Different studies indicate that they may have mainly tumor-promoting functions, but some evidence suggests that they may have certain tumor-suppressive functions in the early stage of tumors. Studying them is therefore fundamental, but far from simple, given their heterogeneity. Gil Friedman of the Israeli Weizmann Institute tried to understand how specific subtypes of CAF exert their functions and especially if and how changes in their composition affect disease progression and response to therapy: to do this, he used mice with breast cancer, from which thousands of CAFs at several timepoints along tumor progression have been extracted and analyzed.
The analysis, conducted with single-cell RNA-sequencing of single cells, confirmed the existence of different subsets of CAF and demonstrated that the transcriptional programs of these subsets change over time, shifting from an immune-regulatory program at earlier timepoints to wound-healing and antigen-presenting programs at later timepoints. “The composition and functions of the CAF are therefore dynamic,” says Friedman. “We also found the two main CAF subsets in human breast tumors, wherein their ratio was associated with disease outcome. This association was particularly correlated with BRCA mutations in triple-negative breast cancer. Therefore, our findings indicate that the diverse composition of CAFs in breast cancer changes over time as tumors progress and that these changes are linked to disease outcome”.