Tumor metastasis: the secret of time and space

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For the treatment of primary tumors, there are many methods: surgical resection as the first-line treatment, combined with radiotherapy, chemotherapy, and targeted therapy as the back-line or adjuvant treatment. These methods have formed a paradigm for the treatment of solid tumors. However, for metastatic tumors, the existing treatments have little effect.

Why do tumors metastasize? Although there are many theories, this problem is still the most mysterious part of the tumor. The physical migration of tumors from the primary site to other tissues and organs begins its colonial stage. In the new environment, it is not wise to quickly transform the new environment to serve itself and drain all the resources. As the resources are exhausted, the tumor will die out together with the host. But in most cases, the tumor chooses this path of no return, It retains the evolutionary power of colonization and doesn't care about destroying an individual. Chaffer CL and Weinberg RA discussed these problems (1), but they still don't seem to go beyond this cognitive scope. They put the process of metastasis into two stages. They said that after the tumor transforms the phenotype, it invaded the blood system and physically migrated, and then colonized. Although the process of colonization was inefficient, it was far more complex than expected, The relationship between the microenvironment of the primary tumor and the new microenvironment is very subtle. The plasticity of tumor cell phenotype and the ability to escape from the immune surveillance make many treatments at a loss (2).

There may not be a single driving factor for tumor metastasis. These driving factors have both spatial heterogeneity and temporal continuity. It may be just a blind attempt to practice the functional research of a single gene or the deep sequencing of the whole genome of an individual. Tracing back to the origin is a way of thinking. Lu MY et al took cancer of unknown primary (CUP) as the research object and developed Tumor Origin Assessment via Deep Learning (TOAD). The algorithm can use tumor histological sections for graphic training. For metastatic tumors, the accuracy of toad is 82.8%, At the same time, its detection capability based on routine histology is close to the report of genome prediction (3)

Tumor biology interacts with the tumor microenvironment. For example, in some cases, cells in the center of the tumor do not have high proliferation and invasiveness, but when the same cell is at the edge of the tumor, it has proliferation and invasiveness. In tumor tissues, a series of single-cell gene sequencing studies also show that the types and numbers of immune cells in tumor tissues also have great heterogeneity (4-6). Therefore, the spatiotemporal characteristics of tumors need to be paid more attention to in the study of tumor metastasis. A recent project based on microarray spatial transcriptomics and single-cell RNA sequencing demonstrated the histological map of pancreatic ductal adenocarcinoma (PDAC) in three dimensions. By establishing the identification and mapping relationship between cell subpopulations and tissue region-specific genes explained by single-cell sequencing, the spatial transcriptomics map can be drawn. This is similar to the difference between the early satellite and the present high-resolution satellite. Every researcher and doctor was provided a bird's-eye view and accuracy. It can be imagined that the black box of tumor metastasis can be more transparent when combined with the same high-resolution scanning of metastatic tumor and microenvironment, or with the monitoring of circulating tumor cells on the metastasis path (7).

References:

1, Chaffer CL & Weinberg RA. Science. 2011;331:1559-1564.

2, Ma B. Semin Cancer Biol. 2020;60:138-147.

3, Lu MY, et al. Nature. 2021 May 5.

4, Liu R et al. Nat Commun. 2021;12:2559.

5, Hornburg M et al. Cancer Cell. 2021 Apr 27.

6, Wu F, et al. Nat Commun. 2021;12:2540.

7, Moncada R, et al. Nat Biotechnol. 2020;38:333-342.