Editors' ChoiceNeuroscience

Complex CAFs

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Science Signaling  06 Jul 2021:
Vol. 14, Issue 690, eabk2490
DOI: 10.1126/scisignal.abk2490

Diversity among cancer-associated fibroblasts from cholangiocarcinomas reveals distinct roles in tumor progression.

The role of cancer-associated fibroblasts (CAFs) in tumor progression is increasingly appreciated; however, CAFs are highly heterogeneous, making their characterization and therapeutic exploitation challenging. Using a transgenic mouse model and cells from patients, Affo et al. have uncovered complex but illuminating profiles of CAFs in cholangiocarcinoma, a highly aggressive and fibrotic tumor in the liver. Cholangiocarcinoma CAFs originated from hepatic stellate cells but were functionally diverse. By single-cell RNA sequencing that was assessed for enrichment in notably inflammatory-, growth factor–, and cytokine pathway–associated gene expression, some CAF subpopulations clustered into distinct groups, whereas others overlapped groups or did not fit any group. Tests of the implicated mechanisms suggested that this diversity in CAF subtype has markedly distinctive effects on their role in tumor growth. “Inflammatory” CAFs, for example, were confirmed to promote tumor growth (specifically, tumor cell proliferation) through the expression and secretion of the growth factor HGF and activation of its receptor MET on cholangiocarcinoma cells, indicating a direct CAF-tumor interaction. In contrast, neither of the pathways implicated for “myofibroblastic” CAFs promoted tumor growth, indicating an indirect CAF-tumor interaction. These findings cast some light onto the depth of complexity of CAFs and their roles in cancer progression and reveal potential strategies for treating this clinically challenging tumor.

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