{Reference Type}: Journal Article
{Title}: ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.
{Author}: Menche C;Schuhwerk H;Armstark I;Gupta P;Fuchs K;van Roey R;Mosa MH;Hartebrodt A;Hajjaj Y;Clavel Ezquerra A;Selvaraju MK;Geppert CI;Bärthel S;Saur D;Greten FR;Brabletz S;Blumenthal DB;Weigert A;Brabletz T;Farin HF;Stemmler MP;
{Journal}: EMBO Rep
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 27
{Factor}: 9.071
{DOI}: 10.1038/s44319-024-00186-7
{Abstract}: The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers are reduced. Single-cell transcriptomics, histological characterization, and in vitro modeling reveal a crucial role of ZEB1 in CAF polarization, promoting myofibroblastic features by restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases NFκB-mediated cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, offering a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.