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

Area of Science:

• Oncology
• Genetics
• Cancer Biology

Background:

• Metastasis is a primary driver of cancer mortality, necessitating a deep understanding of its origins.
• The prevailing hypothesis of single-cell origin for metastatic tumors is increasingly challenged by evidence supporting multicellular origins.
• Quantifying the number of founder cells colonizing a metastatic tumor remains an open research question.

Purpose of the Study:

• To develop and validate a method for quantifying the founder cell population size in metastatic tumors.
• To investigate the cellular origins of metastasis using paired whole-exome sequencing data.
• To explore the relationship between founder cell number and tumor genetic similarity, potentially explaining variable drug responses.

Main Methods:

• Development of a computational method to estimate founder cell population size from paired primary and metastatic tumor whole-exome sequencing (WES) data.
• Utilized a "single bottleneck followed by rapid growth" metastatic model for quantification.
• Validated the method using simulation studies and applied it to WES data from four colorectal cancer patients.

Main Results:

• All analyzed colorectal cancer patient samples supported a multicellular origin of metastasis.
• The estimated founder cell population size ranged from 3 to 17 cells across the patient samples.
• The wide range of founder sizes suggests significant variations in genetic similarity between primary and metastatic tumors within the same individuals.

Conclusions:

• Metastasis commonly arises from a multicellular origin, challenging the single-cell hypothesis.
• The developed method provides a quantitative measure of the founder cell population size.
• Estimated founder cell numbers and resulting genetic heterogeneity may explain differential drug responses observed between primary and metastatic tumors.