L1CAM Defines the Regenerative Origin of Metastasis-initiating Cells in Colorectal Cancer

Overview

Journal Nat Cancer

Specialty Oncology

Date 2020 Jul 14

PMID 32656539

Citations 114

Authors

Karuna Ganesh

Harihar Basnet

Yasemin Kaygusuz

Ashley M Laughney

Lan He

Roshan Sharma

Kevin P ORourke

Vincent P Reuter

Yun-Han Huang

Mesruh Turkekul

Ekrem Emrah Er

Ignas Masilionis

Katia Manova-Todorova

Martin R Weiser

Leonard B Saltz

Julio Garcia-Aguilar

Richard Koche

Scott W Lowe

Dana Peer

Jinru Shia

Joan Massague

Affiliations

Soon will be listed here.

Abstract

Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAM cells partially overlap with LGR5 stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin-REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAM to an L1CAM state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells.

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