Exosome-transmitted FOSL1 from cancer-associated fibroblasts drives colorectal cancer stemness and chemoresistance through transcriptionally activating ITGB4

Abstract

Background Cancer-associated fibroblasts (CAFs) have been proved to facilitate colorectal cancer (CRC) development, either with boosting chemo-resistance by communicating with CRC cells in the tumor microenvironment. However, the underlying molecular mechanisms remain largely unclear. Methods Relative expressions of FOSL1 and ITGB4, either with their correlations in CRC tissues were assessed using qRT-PCR analysis. Also, Kaplan-Meier survival analysis was employed for evaluating the prognosis. Identification of CAFs was determined by the detection of specific makers (α-SMA, FAP, and FSP1) using western blot and immunofluorescence staining. Cell proliferation, self-renewal capacity and cell apoptosis were estimated by CCK-8, sphere-formation and flow cytometry assays. Transcriptional regulation of FOSL1 on integrin β4 (ITGB4) was confirmed using ChIP and dual-luciferase reporter assays. Results Increased FOSL1 and ITGB4 in CRC tissues was both positively correlated with poor prognosis of CRC patients. Interestingly, FOSL1 was enriched in the CAFs isolated from CRC stroma, instead of ITGB4. Co-culture CRC cells with CAFs-conditioned medium (CAFs-CM) increased FOSL1 expression, promoted cell proliferation and oxaliplatin resistance, these effects could be blocked by exosome inhibitor (GW4869). Under the treatment of CAFs-derived exosomal FOSL1, CRC cells exhibited stronger proliferative ability and oxaliplatin resistance. Conclusion Our results uncovered that CAFs-derived exosomes could transfer FOSL1 to CRC cells, thereby promoting CRC cell proliferation, stemness, and oxaliplatin resistance by transcriptionally activating ITGB4.

Exosomes in tumor‐stroma crosstalk: Shaping the immune microenvironment in colorectal cancer

“…Potential strategies could involve targeting their formation, release, or uptake, as well as the bioactive contents they transport, aiming to improve CRC management 92 . Preclinical evidence has shown that agents like GW4869, which suppress exosome release, can diminish the tumor‐promoting actions of CAFs in CRC 89 . Further, blocking the uptake of CAF‐derived exosomes or neutralizing their cargos also showed therapeutic benefits.…”

“…CAFs-derived exosomal FOSL1 was validated to enhance the proliferative ability and oxaliplatin resistance of CRC cells. 89 Radiotherapeutic resistance is also a significant challenge in treating CRC, and miR-590-3p plays a crucial role in chemoresistance and radioresistance. Chen et al reported that high expression of miR-590-3p and low expression of CLCA4 were found in CRC tissues and cell lines.…”

“…FOSL1 was enriched in CAFs isolated from CRC stroma, while CRC cells under a co‐culture system with CAFs‐conditioned medium exhibited increased FOSL1, promotive cell proliferation, and reduced apoptosis. CAFs‐derived exosomal FOSL1 was validated to enhance the proliferative ability and oxaliplatin resistance of CRC cells 89 . Radiotherapeutic resistance is also a significant challenge in treating CRC, and miR‐590‐3p plays a crucial role in chemoresistance and radioresistance.…”

“…92 Preclinical evidence has shown that agents like GW4869, which suppress exosome release, can diminish the tumor-promoting actions of CAFs in CRC. 89 Further, blocking the uptake of CAF-derived exosomes or neutralizing their cargos also showed therapeutic benefits. For instance, heparin, a known exosome uptake inhibitor, has shown a decrease in the pro-tumorigenic effects of CAF-derived exosomes in CRC.…”

FOSL1’s Diverse Roles in Glioma/Glioma Stem Cells and Tu-morigenesis: A Comprehensive Review

“…Upon transferring these to CRC cells, they observed a significant increase in stemness, cell proliferation, and resistance to oxaliplatin. FOSL1 facilitates these effects by promoting integrin β4 (ITGB4) transcription [112].…”