A common feature shared by cancer and obesity is deregulation of cellular homeostasis, including cell proliferation, cell growth, cell metabolism, and cell death; while liver regeneration involves robust proliferation without tumorigenesis. Tumor suppressors such as pRb and p53, oncoproteins such as Ras and Myc, and organ size regulators such as Yap, are the major regulators of cellular homeostasis. We aim to understand how these regulators function with the goals to improve clinical success in treating cancer, treating obesity, and cell therapy with hepatocyte transplantation.
In the cancer field, we are identifying treatment strategies for cancers that have genetically inactivated pRb and p53. pRb and p53 are the two major tumor suppressors. Their functions are activated by most oncogenic events and they implement most and best cells’ antitumor mechanisms. When prostate cancers progress, RB1 and TP53 (genes encoding pRb and p53) are more and more frequently inactivated together (ref 11). On the other hand, all small cell lung cancer (SCLC) co-inactivate RB1 and TP53. These findings explain why advanced prostate cancer and SCLC are among the deadliest cancers in modern medicine.Since it is not feasible to reintroduce RB1 and TP53 back into all cells in a cancer, these frequent features have not led to targeted therapies. Chemotherapies are the only treatment for these cancers but they quickly lose effectiveness. SCLC was designated as one of the two “recalcitrant cancers” by the 2012 US Congress.
We generated mouse prostate cancer and SCLC models by deleting Rb1 and Trp53 in the respective organs to identify mechanisms that can still inhibit these cancers. We showed that combining deletion of Skp2, which is a target of repression by pRb, completely blocked tumorigenesis in the absence of pRb or both pRb and p53 (refs 2, 5, 7, 8). Mutating p27T187 to an alanine, which prevents recognition of p27 by Skp2 but does not harm mouse development and life span (ref 9), also significantly inhibited pRb and p53 doubly deficient prostate tumorigenesis and in cancer organoids (ref 11). SCLC originates from neuroendocrine cells. Using mouse embryonic brains, we found that Skp2 deletion and Rb1 deletion induces synthetic lethal apoptosis that remains effective when p53 is additionally deleted (ref 10). Ongoing studies aim to target functions of Skp2 in regulating p27 degradation, regulating cancer cell metabolism, and regulating epithelial-to-mesenchymal transition to inhibit pRb and p53 doubly deficient prostate cancer and SCLC. At the same time, we are translating mouse model findings to patients on the organoid platform side by side, in order to increase the predictive values of human cell experiments to better rationalize clinical trials.
In the obesity field, we are studying the function of pRb in hypothalamus neurons. These neurons form circuits to positively and negatively regulate energy balance, and it has been suggested that high fat diet could directly disrupt homeostasis of these neurons, leading to diet induced obesity, explaining why dieting commonly fails. We discovered that high fat diet can activate kinases in these neurons to phosphorylate and functionally inactivate pRb. In this context, inactivation of pRb induces degenerative changes in these neurons. When we deleted Rb1 in POMC neurons, the mice increased their food intake and become obese, demonstrating that pRb functions to maintain POMC neuron homeostasis to suppress obesity. To our surprise, in AGRP neurons, which reside together with POMC neurons in hypothalamus and functionally antagonize POMC neurons to reduce the desire to feed, deletion of pRb did not harm their homeostasis. Based on these findings (ref 6, in collaboration of with Dr. Chua of the Einstein Diabetes Center), we are identifying the kinases that phosphorylate pRb in POMC neurons after high fat feeding, and establishing techniques to prevent pRb phosphorylation following high fat feeding. Through these studies, we aim to prevent and treat diet induced obesity.
The liver has remarkable ability to regenerate when 70% of it is resected. This regenerative capability has important implication to tumorigenesis and regenerative medicine. Since the supply of donor liver is far smaller than the demand, hepatocyte transplantation is the best approach to treating liver failure and liver defects. We showed that by deleting the cyclin-dependent kinase inhibitor p27, hepatocytes were stimulated to proliferate more in the host liver to save mice from liver failure (ref 1). Unfortunately, deleting p27 also increased liver cancer burden during liver carcinogenesis by chronic HBV or carcinogen DEN (ref 3, 4). In collaboration with Dr. Shafritz of the Einstein Liver Center, we are now studying the liver size regulator YAP to determine its ability to increase hepatocyte proliferation following transplantation and its associated liver cancer risk.
More Information About Dr. Liang Zhu
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Albert Einstein College of Medicine
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