RESEARCH

Cancers are traditionally studied in the lab using cells derived from highly aggressive cancers and grown in a dish. “Organoids” are three-dimensional cultures that can be derived from any patient’s cancer and reproduce key aspects of the patient’s disease ( Am J Physiol Cell Physiol. 2019).

CRISPR/Cas9 genome editing technology has revolutionized cancer research by permitting rapid and efficient modeling of cancer-associated genes. We developed new ways to study colon cancer by editing organoids using CRISPR/Cas9 technology and then transplanting them into mice. These in vivo tumors progress from adenoma (i.e., precancerous polyp) to cancer, to local invasion, to distant metastasis, which is very similar to human disease. We also developed methods to directly induce cancer-associated mutations in the colon using CRISPR/Cas9 gene editing ( Nature Biotechnology 2017, Nature Protocols 2018).

These tools have been widely used by scientists for studies of the tumor microenvironment in colorectal cancer (Cancer Cell 2019); the effect of aging on the intestinal stem cell niche (Nature 2019); and the genetics of sessile serrated cancer progression (Gut 2019). We are applying our transplantation and CRISPR/Cas9-based models of cancer to study genetic events that underlie cancer progression and metastasis.

Photo credit: Steffen Rickelt, Jatin Roper, Ömer Yilmaz, Richard Hynes. This image shows a section through a mouse liver in which human colorectal cancer-derived organoids (orthotopically transplanted in the mouse colon) have spread. This liver metastasis shows the invading tumor front (brown tumor cell) – growing from the top of the images towards the bottom – embedded in increasing surrounding connective tissue (green fibers). Red round shapes in the lower part of the image indicate human tumor cells and the mouse hepatocytes. Slight green staining in the lower part of the image shows connective tissue that surrounds blood vessels in normal liver tissue. This image won the 2016 Vector Laboratories Photo Contest.

Specific cancer cell subpopulations function as cancer stem cells, based on their ability to reconstitute the entire tumor. Work from our research group and others has demonstrated using lineage tracing techniques that the cell surface receptor Lgr5 marks a stem cell subpopulation in precancerous adenomas ( Nature Biotechnology 2017). Furthermore, a growing body of evidence suggests that tumor stromal cells such as fibroblasts, immune cells, and telocytes play important roles in colon carcinogenesis. We are using lineage tracing, single cell sequencing, and metabolic profiling to study the role of tumor heterogeneity in colorectal cancer initiation, progression and metastasis.

Photo credit: Leah Caplan, Jatin Roper, Inbal Avraham-Davidi, Sebastian Santos, Ömer Yilmaz, Aviv Regev. Combining computer vision with single-cell genome sequencing allows researchers to better understand how cells function and interact within the context of their surrounding environment. In this image, colon cancer cells (green) from a genetically engineered colon cancer model have been sequenced and fluorescently marked. Yellow tags identify stem-like qualities while red show active proliferation. Together, they present a snapshot of a tumor’s dynamic properties. We use this information to determine which biological factors contribute to tumor growth and cancer progression. This image won the 2018 Koch Institute Image Award.  

Obesity is a major risk factor for cancer, including colorectal cancer. We found that diet-induced obesity activates PPAR-delta signaling in intestinal stem and progenitor cells, which increases the ability of these cells to undergo oncogenic transformation upon loss of the tumor suppressor gene Apc (Nature 2016).

Obesity may also promote colorectal cancer development through local interactions between intestinal stem cells and immune cells. We are interested in understanding mechanisms by which obesity regulates the functions of intestinal stem cells in normal homeostasis and in diseases such as cancer.  

This image shows intestinal organoids (3D cultures) from mice with high fat diet-induced obesity.