Guasch Lab

We are addressing a novel concept in the area of the transitional epithelium associated with tumor formation: we hypothesize that this region represents a niche for stem cells receiving input from two types of epithelium, and this creates an environment sensitive to tumorigenesis. We have recently found that a population of slow-cycling cells resides in the anal epithelium at the transition with the rectum [Runck et al., Cell Cycle 2010]. We are addressing whether these cells exhibit stem cell activities and we are determining their transcriptional profile to identify candidates responsible for increased tumor formation at this region.

We are using the mouse as a model system to investigate the role of stem cells in tumor development. Our long-term goal is to understand whether skin cancers arise from stem cells and whether tumors maintain stem cells, using a combination of genetics and biochemical studies. Understanding where cancers come from and how they progress is a prerequisite to developing improved clinical treatments. Squamous cell carcinoma arises in stratified squamous epithelia of the body, and is one of the most common malignancies in humans with some of the poorest prognoses. They are frequently found at epithelial transition zones (TZs), where one type of epithelium changes to another. The underlying mechanisms for this increased tumor susceptibility are unknown. We have recently generated a mouse cancer model by deleting the essential receptor (TβRII) for TGFβ signaling in stratified epithelia. Interestingly, two tissues, the epidermis of the back skin and the anogenital epithelium, responded very differently. In the anogenital region, squamous cell carcinomas develop spontaneously between 4-9 months of age, which recapitulate epithelial cancer of the human anogenital region. We found that spontaneous squamous cell carcinoma in the TβRII deficient mice frequently arose within transitional zones between two merging but distinct epithelial tissue types. Tumor susceptibility was especially prominent at the juncture of mucosal stratified squamous epithelium of the anal canal and simple epithelial tissue of the large intestine.

Our long-term goal will address if normal resident adult tissue stem cells from the anal transitional epithelium may be a special target for carcinogenic insults.

Anorectal malformations affect one in 5,000 babies, and the etiology is unknown. We have identified specific markers for early anal epithelium that may play a crucial role in regulating epithelial morphogenesis and for establishing the boundary between the squamous epithelium of the anal canal and the simple epithelium of the rectum. We are using conditional approaches to technology in mice and human anorectal malformation samples from the Colorectal Center to investigate the role of those genes in the formation of the anal transitional epithelia. We are also actively collaborating with the Digestive Health Center.

Anorectal malformations (ARMs) occur in one in 5,000 live births. Persistent cloaca, the most complex ARM, occur in one in 50,000 live female births. It is the incomplete separation of the embryonic cloaca into urethral, vaginal and rectal openings, resulting in a common channel that opens into the perineum.  The histological constituents of the common channel include the submucosa, mucosa and epithelium. The length of the common channel correlates with the prognosis in terms of bowel control, urinary control, and sexual and reproductive capabilities.

Our goal is to determine the type of epithelium found in the common channel using histological approaches on human persistent cloaca samples provided by Alberto Peña and Marc Levitt of the Colorectal Center and to determine which signaling pathways may contribute to the malformation. We are also collaborating with the Division of Pathology and Pathology Core in interpretation of the histological results.