Abstract
Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). How tumor cells disseminate within the lymphatic network remains largely unknown. Here, we analyze the subclonal structure of 94 tumor samples, covering the primary tumors, lymph node metastases (LNMs), and liver metastases from 10 CRC patients. We portray a high-resolution lymphatic metastatic map for CRC by dividing LNMs into paracolic, intermediate, and central subgroups. Among the 61 metastatic routes identified, 38 (62.3%) are initiated from the primary tumors, 22 (36.1%) from LNMs, and 1 from liver metastasis (1.6%). In 5 patients, we find 6 LNMs that reseed 2 or more LNMs. We summarize 3 diverse modes of metastasis in CRC and show that skip spreading of tumor cells within the lymphatic network is common. Our study sheds light on the complicated metastatic pattern in CRC and has great clinical implications.
Highlights
Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC)
To gain a higher resolution of the metastatic network of CRC, lymph node metastases (LNMs) were further classified into paracolic, intermediate, and central subgroups according to their spatial distance from the primary tumor (Fig. 1b, see Methods)[30]
Given that intratumor heterogeneity is well characterized in CRC, we isolated multi-region samples from the primary tumor (2–5 regions) and liver metastases (2 regions) according to the tumor size in order to capture subclones that may otherwise be missed by single-region sequencing (Fig. 1b)
Summary
Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). Current CRC management guidelines are based on this model, in which lymph node metastasis (LNM) serves as an important prognostic factor and triggers lymphadenectomy to prevent tumor cells from further spreading to distant organs[12]. A recent study using indel mutations in hypermutable, noncoding polyguanine repeats challenged this model by showing that lymphatic and distant metastases had distinct clonal origins in 65% (11/17) of CRC patients[13] These results suggest that tumor cells in the primary tumor can directly spread to distant organs without traveling through the lymph nodes, questioning the necessity of lymphadenectomy to prevent disease progression. Most current studies focus on the comparison between LNMs and distant metastases but how tumor cells disseminate within the lymphatic network is less explored, and whether all LNMs have the same metastatic potential remains largely unknown. Our results reveal the detailed metastatic process of CRC and provide important clinical implications for CRC management
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