Calvin Kuo Laboratory @ Stanford University

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CANCER ORGANOIDS

We and others have defined methods to grow a variety of normal tissues in a dish as 3–dimensional “organoids” or mini–organs. These organoids are clusters of cells that recapitulate the architecture and multilineage differentiation of organs in the body.

One of many methods that we use involves an “air–liquid interface” where organoids are grown in a gel and exposed directly to air instead of being submerged underneath nutrient medium (Nature Medicine 2009; Nature Medicine 2014).

This allows numerous tissues such as intestine, stomach and pancreas to be grown as organoids with both epithelium and supporting mesenchymal stroma, recapitulating the normal structure of organs.

Growing Normal Tissues as Organoids

Intestine Stomach Pancreas

Growing normal tissues in a dish certainly has applications such as regenerative medicine and organ transplantation. However, we have also used organoids to model cancer. Indeed, we have converted normal colon, stomach and pancreas organoids into their respective malignancies in the dish by adding combinations of 2–4 cancerous mutations. These cancerous mutations induce the organoids to convert into a tumor–like appearance, to grow and invade aggressively, and even to form tumors when transplanted into mice, all characteristics of human cancers.

Transforming normal organoids into cancer

Being able to convert normal tissues/organoids into cancer in a dish represents a powerful system for discovering and proving the function of new cancer-causing mutations. Tumor cells often have hundreds if not thousands of mutations and other/epigenetic alterations, but only a minority are critical “drivers” that cause cancer, versus the vast majority of irrelevant “passenger” mutations. With collaborators we utilize computational and systems biology principles to interrogate large tumor DNA sequencing datasets to identify candidate cancer driver genes. We then exploit the power of organoids for cancer gene discovery, systematically inserting mutations found in cancer cells (from projects such as TCGA) to test if such mutations successfully convert the organoids to a cancerous phenotype. Accelerating the functional validation of cancer–causing mutation will allow therapies and diagnostics to be developed against these genes.

Testing effects of a oncogenic microRNA

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