Cell Reports: Professor Di Zhu/Jianmin Xu team reveals liver metastasis mechanisms in colon cancer

On August 30, 2022, The team of Professor Zhu Di of the School of Basic Medical Sciences of Fudan University, together with the team of Professor Xu Jianmin of Zhongshan Hospital affiliated to Fudan University, published a research paper

entitled "Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers" at Cell Reports.

Through single-cell sequencing, the important role and mechanism

played by B cells and their subsets in the liver metastasis of left and right colon cancers were discovered.

 

Liver metastases are one of the most important causes of colon cancer prognosis, with high

incidence and mortality.

The treatment of liver metastasis in colon cancer has become a medical problem in the world and needs to be broken through

urgently.

Therefore, it is particularly important

to study the mechanism of liver metastasis in colon cancer and improve the prognosis of patients.

Due to the different embryos, anatomy, and physiological functions of the left and right colons, left and right colon cancers show great heterogeneity

.

The treatment regimen and prognosis of liver metastases in left and right colon cancers are also different, but the mechanism is still unclear

.

 

Studies in recent years have shown that the tumor immune microenvironment plays an important role

in the progression of cancer.

However, there is still a lack of
immune microenvironment studies between liver metastasis of colon cancer and left and right colon cancers.

Secondly, which important immune cells affect the liver metastasis of colon cancer, and the difference between left and right colon cancers, is still unclear
.

 

The authors first detected and compared the immune microenvironmental composition of primary lesions of patients with liver metastases and no metastases by single-cell sequencing, and found that B cells and their subsets of activated B cells in the samples of colon cancer primary lesions in patients with liver metastasis were significantly reduced
.

Immunohistochemical analysis showed that the infiltration of B cells and activated B cells in the primary lesions of colon cancer was significantly related
to the better prognosis of patients with liver metastases in colon cancer.

 

Through the analysis of the differentiation trajectory of B cells, the authors found that the differentiation of B cells is closely related to liver metastasis
.

Moreover, in the liver metastasis of left and right colon cancer, the differentiation of B cells undergoes different processes
.

All of these processes involve Wnt, an important signaling pathway
.

 

Through further analysis, the authors found a group of cells associated with the differentiation of activated B cells into plasma cells
.

This group of cells is only highly expressed in the IgG heavy chain gene
.

Because the integrity of IgG requires the participation of light and heavy chains, this group of cells expresses incomplete IgG
.

The authors found that its function was strongly associated with liver metastases and named this group of immature plasma cells iMPA (immature plasma cell population alpha
).

Based on this, the authors created a score evaluating the IgG heavy/light chain ratio, and not only found that the heavy/light chain ratio led to heterogeneity of left and right half colon cancer, which was associated with liver metastasis of colon cancer, but also used the database to verify the predictive prognosis value
of this score in pan-cancer species.

 

The authors constructed a mouse model of liver metastases, demonstrating that activating B cells can significantly inhibit liver metastases
.

The authors found that the Wnt and TGFβ signaling pathways that inhibit tumor cells can promote the migration of activated B cells through the SDF-1-CXCR4 axis, thereby enhancing the anti-tumor ability
of activated B cells.

 

Figure 1.
Graphic abstract

 

In summary, this study revealed a significant reduction in activated B cells in the primary foci of colon cancer liver metastasis by single-cell sequencing technology, and for the first time found a novel B cell subset iMPA
associated with left and right colon cancer heterogeneity and colon cancer liver metastasis.

Further studies have shown that activating B cells is effective in inhibiting colon cancer liver metastasis
.

Inhibition of the Wnt and TGFβ pathways promotes the migration
of activated B cells through the SDF-1-CXCR4 axis.

This study elaborates the important role played by B cell subsets in the immune microenvironment of primary foci of liver metastases in colon cancer, and provides a theoretical basis
for B cell subsets to become potential targets for the prevention and treatment of liver metastases in colon cancer.

 

Professor Zhu Di of the School of Basic Medicine of Fudan University and Professor Xu Jianmin of Zhongshan Hospital affiliated to Fudan University are the co-corresponding authors
of this article.

Xu Yuqiu of Zhongshan Hospital Affiliated to Fudan University, Wei Zhuang of Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Feng Mei of School of Basic Medical Sciences of Fudan University, Zhu Dexiang of Zhongshan Hospital Affiliated to Fudan University, and Mei Shenglin of School of Life Science and Technology of Tongji University are the co-first authors
of this article.

 

The corresponding author of this paper and Lead contact, Zhu Di, a national young distinguished expert, dedicated to the study of tumor immunopharmacology, his laboratory in the direction of tumor immuno-innovative therapy to carry out a series of research, based on the previous first/co-author article Nature Medicine, Science Translational Medicine, after returning to China to build a research platform for tumor immunopharmacology, The results of the corresponding authors' research have been published in Cancer Discovery, Signal Transduction and Targeted Therapy, Science Advances, Cell reports, Oncogene, Journal of Experimental & Clinical Cancer Research, Pharmacological Research, British Journal of Pharmacology and other magazines
.

It has also completed the transformation of some of the research results, two of which have entered non-registered clinical trials
.

 

References: Xu et al., 2022, Cell Reports, 40, 111295.doi.org/10.1016/j.celrep.2022.111295

 

Typography: Jiang Zhou

Execution: Traveller