Abstract
Cancer-associated fibroblasts (CAFs) exert a key role in cancer progression and liver metastasis. They are activated in the tumor microenvironment (TME), but their prometastatic mechanisms are not defined. CAFs are abundant in colorectal cancer (CRC). However, it is not clear whether they are raised from local tissue-resident fibroblasts or pericryptal fibroblasts and distant fibroblast precursors, and whether they may stimulate metastasis-promoting communication. B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is the key transcription cofactor of β-catenin. We studied the TME of CRC with single-cell sequencing and consequently found that Bcl9 depletion caused a pro-tumor effect of CAFs, while inhibition of abnormal activation of Wnt/β-catenin signal through Bcl9 depletion benefited T-cell–mediated antitumor immune responses. We also identified and evaluated four types of CAFs in CRC with liver metastasis. In summary, we demonstrate cell type landscape and transcription difference upon BCL9 suppression in CAFs, as well as how CAF affects cancer associated immune surveillance by inhibition of Wnt signaling. Targeting the Wnt signaling pathway via modulating CAF may be a potential therapeutic approach.
Highlights
Colorectal cancer (CRC) is a widespread malignancy and the third leading cause of cancer mortality worldwide [1]
Cancer-associated fibroblasts (CAFs) are very critical in cancer progression when they are activated in the tumor microenvironment (TME)
CAFs play a key role in cancer progression and metastasis; their prometastatic mechanisms have not been investigated
Summary
Colorectal cancer (CRC) is a widespread malignancy and the third leading cause of cancer mortality worldwide [1]. Most CRCs occur sporadically in patients without family history of intestinal diseases [2]. BCL9 Modulates CAFs in CRC combined with targeted drugs) has improved the treatment of CRC. Combinations of targeted drugs containing epidermal growth factor receptor (EGFR) antibody and vascular endothelial growth factor (VEGF) antibody with chemotherapy such as FOLFIRI, XELOX/CAPOX, or FOLFOX have been shown to prolong survival in patients with CRC [4]. Treatment of patients with advanced recurrent or metastatic CRC is still inadequate. It is necessary to determine molecules and signaling pathways that are critical for CRC and to find new therapeutic targets
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