Cancer Center at Illinois (CCIL) member Lin-Feng Chen published new research reporting an important factor driving chemoresistance for patients with colorectal cancer. The research is published in the journal Oncogene.
Chen’s study found that the protein BRD4—present in certain immune cells—facilitates colorectal tumor resistance to chemotherapy. When removing this protein from mice in the study, the tumors were less aggressive and more sensitive to the chemotherapy drug oxaliplatin. Furthermore, the study revealed that BRD4 helps immune cells produce a protein called PAI-1, which shields the tumor from chemotherapy. For patients with colorectal cancer, those with higher levels of BRD4 and PAI-1 in tumors are more likely to have chemoresistant cancer, the study reports.
From the left: Visiting scholar Dr. Dun Pan (first author of the team’s paper), Cancer Center at Illinois (CCIL) member Lin-Feng Chen, and graduate students, Yanheng Chen and Yiran Zheng (co-authors of the team’s paper)
Essential to Chen’s study is a foundational understanding of the tumor microenvironment (TME) and tumor-associated macrophages (TAMs). The TME, comprising various immune cells, plays a crucial role in shaping an immunosuppressive landscape that promotes tumor development, progression, metastasis, and resistance to therapy. Among the immune cells in the TME, TAMs are the most abundant and are known to exert potent immunosuppressive functions, supporting tumor growth, and immune evasion.
“Our lab has long been interested in the connection between inflammation and cancer, particularly how chronic inflammation contributes to tumor initiation and progression,” shared Chen, professor of biochemistry. “In our previous research, we demonstrated that the epigenetic regulator BRD4 plays a central role in controlling the innate immune response. Our findings led us to hypothesize that BRD4 may similarly regulate the behavior and immunosuppressive activity of TAMs within the TME.”
Colorectal cancer is one of most common cancers in the United States, with an estimated 107,320 new cases expected in 2025. When combining cancer statistics for both women and men, colorectal cancer is the second leading cause of cancer death in the nation.
(Source: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-stastics)
“While most colorectal cancer studies have focused on the intrinsic role of BRD4 in cancer cell proliferation and tumor formation, this study notably demonstrates that inhibiting BRD4, specifically in TAMs rather than in cancer cells, is sufficient to suppress tumor development,” said Chen.
The significance of Chen’s study points in the direction of paradigm shift in cancer therapy: targeting BRD4 in the tumor-supportive functions of immune cells, like TAMs, rather than BRD4 in the tumor cells alone.
“By identifying BRD4 and PAI-1 as critical players in the chemoresistant TME, it opens the door to new combination treatments, biomarker-driven patient selection, and improved outcomes for patients with treatment-resistant cancers,” reported Chen.
For this study, Chen collaborated with former postdoctoral fellow, Dr. Xiangming Hu from Fujian Medical University, and Dun Pan, visiting scholar in Chen’s lab and the first author of the research team’s paper, “BRD4 regulates PAI-1 expression in tumor-associated macrophages to drive chemoresistance in colorectal cancer.”
Building upon the foundation of the findings reported in this paper, Chen’s lab is collaborating with CCIL members Erik Nelson, Andrew Smith, and Hua Wang. Funded by a CCIL Seed Grant, the research team is investigating whether selectively inhibiting BRD4 in TAMs, using small-molecule inhibitors, can reprogram the TME and enhance tumor sensitivity to chemotherapy or immunotherapy.
Editor’s notes:
Lin-Feng Chen is a Professor of Biochemistry in the School of Molecular and Cellular Biology at the University of Illinois Urbana-Champaign, and he is an affiliate of the Carl R. Woese Institute for Genomic Biology. He can be reached at lfchen@illinois.edu.
The paper, “BRD4 regulates PAI-1 expression in tumor-associated macrophages to drive chemoresistance in colorectal cancer,” is available here.
This story was written by Jonathan King, CCIL Communications.