Pten and GUT epithelial physiology

This Project Grant award of $439,049 was provided by the National Cancer Institute (CFDA 93.395 - Cancer Treatment Research) to Oakland University in Michigan. The funding supports research to investigate the role of the PTEN protein phosphatase in regulating the ubiquitination and autophagy of SNAIL/SLUG transcriptional repressor proteins within intestinal epithelial cells. The research aims to elucidate how PTEN deficiency can induce preclinical dysplasia in the intestine, and how loss of immune regulation (e.g. via MyD88 deficiency) can unleash the tumorigenic potential of PTEN deficiency. The project period runs from July 1, 2025 to June 30, 2028 and focuses on advancing the understanding of PTEN's functions in intestinal epithelial physiology and cancer development.

Abstract

Pten is classically considered a lipid phosphatase. Hence, loss of pten perpetuates the PI3K-AKT signaling to promote cell proliferation, causing pre-clinical dysplasia or tumor. On the other hand, emerging evidence suggests that pten has a protein phosphatase activity to regulate the phosphorylation at ubiquitin protein. In this project, we suggest that pten regulates the ubiquitination of snail/slug transcription repressor proteins and the autophagy pathway in intestinal epithelial cells (iecs). Pten deficiency elevates the ubiquitination of snail/slug. By lowering YKT6, pten deficiency also suppresses autophagosome-lysosome fusion to inhibit autolysosome formation. Then, aborted autolysosomes cannot degrade ubiquitinated snail/slug, leading to augmented snail/slug repressors. Consequently, IT represses the cell-junction protein expression, disrupting the cell-cell junction and segregating the IEC from the intestinal epithelium. Regarding the role of pten in tumorigenesis, previous studies suggest that loss of pten gene alone cannot cause tumor development in the intestine. Indeed, IEC-target pten knockout (KO) (ptenδiec/δiec) mice do not develop tumors in the intestine. However, we observed that ptenδiec/δiec mice have enhanced cell growth and pre-clinical dysplasia in the intestine. Human colon cancer tissues have reduced expression of pten and MYD88 (a key immune regulator) compared to normal tissues. Accordingly, ptenδiec/δiec mice develop massive intestinal tumors and metastasis when combined with MYD88-KO. Therefore, our overall hypothesis is that (1) pten deficiency can induce pre- clinical dysplasia, but an immune surveillance mechanism restrains its tumorigenic potential in the intestine. (2) if an immune mechanism is compromised, IT unleashes the tumorigenic potential of the pten deficiency. In parallel, (3) pten deficiency can disrupt the cell-cell junction, allowing the segregation of dysplastic cells from the epithelium. Further, a segregated dysplastic cell migrates to an extra-intestinal organ, developing tumor metastasis. Based on the hypothesis, this R15 application proposes two major research aims: aim 1 investigates the non-classical function of pten in iecs. Aim 2 tests a potential intervention to prevent pten-promoted tumorigenesis and metastasis.