Polyclonality overcomes fitness barriers in Apc-driven tumorigenesis

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Loss-of-function mutations in the Adenomatous Polyposis Coli (APC) tumor suppressor gene initiate intestinal tumorigenesis.
• APC-mutant stem cells outcompete wild-type cells via Wnt antagonist secretion, promoting rapid clonal expansion.
• The prevalence of polyclonal intestinal tumors contradicts the monoclonal expansion model.

Purpose of the Study:

• To investigate the origin and dynamics of intestinal tumors.
• To determine if intestinal tumors arise from single or multiple ancestral cells.
• To understand the role of interclonal interactions in tumor progression.

Main Methods:

• Multicolour lineage tracing in mice combined with chemical mutagenesis.
• Analysis of tumor subclones, Apc mutations, and transcriptional states.
• Introduction of oncogenic Kras mutation to assess tumor origin.

Main Results:

• A significant proportion of intestinal tumors exhibit a multiancestral origin (polyclonal).
• Polyclonal tumors contain subclones with distinct Apc mutations and transcriptional states, driven by KRAS and MYC signaling.
• Polyclonal tumors display accelerated growth dynamics compared to monoclonal tumors.
• Oncogenic Kras mutation leads to predominantly monoclonal tumor formation.

Conclusions:

• Intestinal tumors frequently arise from multiple ancestral cells, challenging the established monoclonal expansion model.
• Interclonal interactions, driven by differential oncogenic pathway activation (e.g., KRAS, MYC), promote tumorigenesis and tumor progression.
• Understanding these non-cell autonomous interactions is crucial for developing effective cancer therapies.