Bottom Line: Scientists at the Sloan Kettering Institute have discovered that the ability of cancers to metastasize to other organs is dependent upon their ability to co-opt natural wound-healing pathways. In a literal sense, metastasis is wound healing gone wrong. These findings provide a novel framework for thinking about metastasis and how to treat it.
Background: Metastasis is responsible for about 90% of all cancer deaths, although not much is known about what makes cancer cells capable of forming metastases. Previous studies from the Massagué lab have shown that a molecule called L1CAM is necessary for numerous types of cancer cells to successfully metastasize to organs. Normal healthy tissues do not typically make L1CAM, but advanced cancers often do. Exactly what triggers the expression of L1CAM has so far been a mystery.
Findings and Method: From looking at human tumor tissues under a microscope, it was clear to the researchers that dividing cells with L1CAM were more common in areas where an epithelial layer was disrupted — that is, wounded. Using a mouse model of colitis, the researchers confirmed that L1CAM is required for normal wound repair. Next, they wanted to know exactly what it is about the wounding process that causes cells to switch on L1CAM. To find out, they turned to a recently developed technology called tissue organoids. Using these organoids, researchers were able to show that simply separating cells from their neighbors was enough to trigger L1CAM production.
Wounds are essentially a breach in the integrity of the epithelial layer of our skin: Cells that are normally linked tightly to each other to form a protective barrier are suddenly separated. Similarly, in metastasis, cells detach from their neighbors and adopt a migratory behavior to reach new locations. The researchers suspect that the wound repair program equips both types of cells to survive this anchorless state. In the first case, it allows cells to move into the breach and make new tissues; in the second, it enables metastatic cells to detach and colonize new destinations.
Since previous researchers had linked cancer growth to wound healing, the SKI scientists asked whether cells that produce L1CAM are necessary to initiate the growth of a primary tumor. Using a mouse model, they found, somewhat surprisingly, that they were not — tumors formed fine without it. However, these L1CAM-making cells were necessary for tumors to metastasize. This led the researchers to conclude that the stem cells that form primary tumors are different from the ones that form metastases.
This major study concludes that metastasis-initiating cells co-opt the body’s natural wound-healing abilities in order to spread. In addition, these findings show that stem cells that generate primary tumors are fundamentally different from those that generate metastases, suggesting that L1CAM is a promising therapeutic target for treating metastatic cancer.
Expert Commentary: “We now understand metastasis as the regeneration of the wrong tissue — the tumor — in the wrong place — distant vital organs,” says Joan Massagué. “This is not just a metaphor. It is literally true in molecular and physiological terms.”
Journal: “L1CAM Defines the Regenerative Origin of Metastasis-Initiating Cells in Colorectal Cancer” was published in the inaugural issue of the journal Nature Cancer, on January 13, 2020.
Authors: Karuna Ganesh, MD, PhD, a physician-scientist in the Molecular Pharmacology Program at Sloan Kettering Institute, is the paper’s first author. Joan Massagué, PhD, Director of the Sloan Kettering Institute, is the paper’s corresponding author.
Funding: This work was supported by National Institutes of Health via grants P01-CA129243 (J.M.), P01-CA094060 (J.M.), P30-CA008748 (MSKCC), K08-CA230213 (K.G.), T32-CA009207 (K.G.), T32-GM007739 (K.P.O. and Y.-H.H.), and F30-CA203238 (Y.-H.H.); a Department of Defense Innovator Award W81XWH-12-0074 (J.M.); the Damon Runyon Foundation; the American Cancer Society; the American Association for Cancer Research; the Conquer Cancer Foundation; the Shulamit Katzman Foundation; Burroughs Wellcome; and the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center at MSK. Dr. Ganesh is an investigator for the Stand Up To Cancer Colorectal Cancer Dream Team. Dr. Massagué is a science advisor for and owns company stock in Scholar Rock.