Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases

Abstract

Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate inter- and intra-lesion heterogeneity for two types of metastases that associate with different clinical outcomes: lymph node and distant organ metastases in human colorectal cancer. We develop a rigorous mathematical framework for quantifying metastatic phylogenetic diversity. Distant metastases are typically monophyletic and genetically similar to each other. Lymph node metastases, in contrast, display high levels of inter-lesion diversity. We validate these findings by analyzing 317 multi-region biopsies from an independent cohort of 20 patients. We further demonstrate higher levels of intra-lesion heterogeneity in lymph node than in distant metastases. Our results show that fewer primary tumor lineages seed distant metastases than lymph node metastases, indicating that the two sites are subject to different levels of selection. Thus, lymph node and distant metastases develop through fundamentally different evolutionary mechanisms.

Spatial profiling of gastric cancer patient-matched primary and locoregional metastases reveals principles of tumour dissemination

“…29 While differentiation between superficial and deep aspects of the tumour was not performed, this study, as well as another similar study performed in colorectal cancer, confirms a distinct model of metastasis with diverse trajectories for lymph node and distant organ dissemination. 30 Our results yielded several findings of potential clinical and biological relevance. First, we observed minimal differences in gene expression between superficial subregions from the same GC.…”

Clonal Evolution and Timing of Metastatic Colorectal Cancer

“…To confirm these patterns, we calculated the RDS (root diversity score) as previously described [ 33 ], to quantify the amount of homogeneity amongst the metastases with multiple sampled regions per tumour available (70%, 21/30 of cases) ( Figure S2b ). As expected, polyclonal metastases had significantly higher RDS values (median 0.21, range 0.01–1), demonstrating higher tumour heterogeneity than monoclonal metastases (median 0.01, range 0–0.44) (BH adjusted p = 0.001, Mann–Whitney U test).…”

“…Polyclonal seeding occurred both synchronously (at the same time) and asynchronously (over multiple waves), arising from distinct spatial regions in the primary tumour. All lymph node metastases that were seeded through polyclonal spread incurred consecutive waves of seeding, possibly due to their geographical proximity to the primary tumour and higher seeding frequency (as the draining lymph nodes encounter higher rates of tumour cells) compared to distant organ sites [ 33 ]. Nascent micrometastases may attract subsequent waves of recurrent seeding for the successful colonisation of a distinct metastatic site [ 40 ].…”

Intranodal pressure of a metastatic lymph node reflects the response to lymphatic drug delivery system

“…However, we have to pay attention to the fact that the relationship between LN metastasis and distant metastasis in humans remain to be elucidated. Some studies have insisted that a weak relationship exists between LN metastasis and distant metastasis, based on phylogenic analysis 34‐36 . In some cases, metastatic cells in regional LN and distant organs originated from common lesions, indicating that some cases of LN metastasis in humans might contribute to distant metastasis 37 …”