Quantification of multicellular colonization in tumor metastasis using exome‐sequencing data

Abstract

Metastasis is a major cause of cancer‐related mortality, and it is essential to understand how metastasis occurs in order to overcome it. One relevant question is the origin of a metastatic tumor cell population. Although the hypothesis of a single‐cell origin for metastasis from a primary tumor has long been prevalent, several recent studies using mouse models have supported a multicellular origin of metastasis. Human bulk whole‐exome sequencing (WES) studies also have demonstrated a multiple “clonal” origin of metastasis, with different mutational compositions. Specifically, there has not yet been strong research to determine how many founder cells colonize a metastatic tumor. To address this question, under the metastatic model of “single bottleneck followed by rapid growth,” we developed a method to quantify the “founder cell population size” in a metastasis using paired WES data from primary and metachronous metastatic tumors. Simulation studies demonstrated the proposed method gives unbiased results with sufficient accuracy in the range of realistic settings. Applying the proposed method to real WES data from four colorectal cancer patients, all samples supported a multicellular origin of metastasis and the founder size was quantified, ranging from 3 to 17 cells. Such a wide‐range of founder sizes estimated by the proposed method suggests that there are large variations in genetic similarity between primary and metastatic tumors in the same subjects, which may explain the observed (dis)similarity of drug responses between tumors.

Genetic diversity through social heterosis can increase virulence in RNA viral infections and cancer progression

“…This may explain dissimilarity in drug responses between tumours. [ 74 ] Group-level selection for the most effective social genome against chemotherapy. (O5) colorectal The CTC clusters contain parenchymal cancer cells together with immune cells, cancer-associated fibroblasts, tumour stroma and platelets that reflect the heterogeneity of their primary tumour.…”

“…In cancer, the evidence for social heterosis is strongly suggestive ( table 3 ). Most tumours are heterogeneous ecosystems of interactive cell populations [ 74 , 113 ]. In many cancers, increased tumour diversity correlates with faster growth rate, higher malignancy and higher resistance to therapy ( table 3 ).…”

“…Thus, even with strong selective pressures for driver mutations, tumour diversity is maintained throughout cancer progression [64,115]. Indeed, interactions between tumour subclones contribute to faster and more efficient metastases in many cancers [74,88,114,118]. Several cancers show strong evidence for social genomes and patterns of diversity which correlate with increased aggression of tumours (table 3).…”

“…These subclones are the most common, suggesting their presence requires colorectal All samples from colorectal cancer patients found a multicellular origin of metastasis, ranging from 3 to 17 cells. This may explain dissimilarity in drug responses between tumours [74].…”

Dataset of tugHall simulations of cell evolution for colorectal cancer

“…CASE I: “Mutated_cell” with few exceptions, the tumor cell population(s) in a human, including metastatic one, are originated from only one cell (clonal mutations) [5] . So, the clones usually have a single common ancestor.…”