Targeting FAPα-expressing hepatic stellate cells overcomes resistance to antiangiogenics in colorectal cancer liver metastasis models

Abstract

Vessel co-option has been demonstrated to mediate colorectal cancer liver metastasis (CRCLM) resistance to anti-angiogenic therapy. The current mechanisms underlying vessel co-option have mainly focused on the "hijacker" tumor cells, whereas the function of the "hijackee" sinusoidal blood vessels has not been explored. Here, we found that the occurrence of vessel co-option in bevacizumab-resistant CRCLM xenografts was associated with increased expression of fibroblast activation protein alpha (FAPα) in the co-opted hepatic stellate cells (HSCs), which was dramatically attenuated in HSC-specific conditional Fap-knockout mice bearing CRCLM allografts.Mechanistically, bevacizumab treatment induced hypoxia to upregulate the expression of fibroblast growth factor-binding protein 1 (FGFBP1) in tumor cells. Gain-or lossof-function experiments revealed that the bevacizumab-resistant tumor cell-derived FGFBP1 induced FAPα expression by enhancing the paracrine FGF2-FGFR1-ERK1/2-EGR1 signaling pathway in HSCs. FAPα promoted CXCL5 secretion in HSCs, which activated CXCR2 to promote the epithelial-mesenchymal transition of tumor cells and the recruitment of myeloid-derived suppressor cells. These findings were further validated in CRCLM patient-derived tumor tissues. Targeting FAPα + HSCs effectively disrupted the co-opted sinusoidal blood vessels and overcame bevacizumab resistance.Our study highlights the role of FAPα + HSCs in vessel co-option and provides an effective strategy to overcome the vessel co-option-mediated bevacizumab resistance.

Single‐cell RNA sequencing reveals the heterogeneity of epithelial cell and fibroblast cells from non‐ to metastatic lymph node OTSCC

“…In this research, the program SCENIC 23 was employed to identify TFs and their corresponding targets that exhibit elevated levels of activity in a specific subtype of CAFs compared to other subtypes. It was revealed that the distribution of EGR1 was present in all clusters, suggesting its potential role in mediating RNA in fibroblasts to promote cell cycle progression and carcinogenesis in different malignancies 31,32 . Our study revealed an enrichment of CREB5, RUNX3, and HIVEP2 in iCAFs, which were previously been implicated in promoting invasiveness and metastasis in colorectal cancer and head and neck malignancies 33,34 .…”

“…It was revealed that the distribution of EGR1 was present in all clusters, suggesting its potential role in mediating RNA in fibroblasts to promote cell cycle progression and carcinogenesis in different malignancies. 31,32 Our study revealed an enrichment of CREB5, RUNX3, and HIVEP2 in iCAFs, which were previously been implicated in promoting invasiveness and metastasis in colorectal cancer and head and neck malignancies. 33,34 The expression level of TFs MYF6, MYF5, MYOD1, and MYOG were found to be significantly elevated in myCAFs, with their respective target genes serving as biomarkers for myofibroblast.…”

Cells in the liver microenvironment regulate the process of liver metastasis

“…37,87 Interactions between cancer cells and HSCs maintain the activation phenotype of HSCs in a positive feedback manner, forming a microenvironment that promotes liver metastasis. 88,89 Vasodilator-stimulated phosphoprotein (VASP) is a regulator of the actin cytoskeleton. Tu et al found that CRC cells induced VASP upregulation in HSCs, sensitizing HSCs to TGF-β.…”

“…CAFs consist of mesenchymal fibroblasts and α‐smooth muscle actin (α‐SMA)‐positive myofibroblasts, which are major components of the metastatic CRC tumor microenvironment 37,87 . Interactions between cancer cells and HSCs maintain the activation phenotype of HSCs in a positive feedback manner, forming a microenvironment that promotes liver metastasis 88,89 . Vasodilator‐stimulated phosphoprotein (VASP) is a regulator of the actin cytoskeleton.…”

Novel 68Ga-Labeled Pyridine-Based Fibroblast Activation Protein-Targeted Tracers with High Tumor-to-Background Contrast

“…Overexpression of FAP in tumors has been shown to promote tumor growth, angiogenesis [ 11 ], and metastasis [ 12 ]. Silencing FAP has been shown to induce tumor cell apoptosis [ 13 ], indicating its important role in cancer cells survival. Moreover, a high level of FAP expression in the stroma is associated with aggressive disease progression and recurrence in colorectal cancer [ 14 ].…”