The Protocadherin 10 (PCDH10) is inactivated often by promoter hypermethylation in various human tumors, but its possible functional role as a tumor suppressor gene is not established. In this study, we identify PCDH10 as a novel Wnt pathway regulatory element in endometrioid endometrial carcinoma (EEC). PCDH10 was downregulated in EEC tumor cells by aberrant methylation of its promoter. Restoring PCDH10 levels suppressed cell growth and triggered apoptosis in EEC cells and tumor xenografts. Gene expression profiling revealed as part of the transcriptomic changes induced by PCDH10 a reduction in levels of MALAT1, a long noncoding RNA, that mediated tumor suppression functions of PCDH10 in EEC cells. We found that MALAT1 transcription was regulated by Wnt/β-catenin signaling via TCF promoter binding and PCDH10 decreased MALAT1 by modulating this pathway. Clinically, MALAT1 expression was associated with multiple parameters in patients with EEC. Taken together, our findings establish a novel PCDH10–Wnt/β-catenin–MALAT1 regulatory axis that contributes to EEC development. Cancer Res; 74(18); 1–15. ©2014 AACR.

Extracellular tumor acidosis largely results from an exacerbated glycolytic flux in cancer and cancer-associated cells. Conversely, little is known about how tumor cells adapt their metabolism to acidosis. Here, we demonstrate that long-term exposure of cancer cells to acidic pH leads to a metabolic reprogramming toward glutamine metabolism. This switch is triggered by the need to reduce the production of protons from glycolysis and further maintained by the NAD+-dependent increase in SIRT1 deacetylase activity to ensure intracellular pH homeostasis. A consecutive increase in HIF2α activity promotes the expression of various transporters and enzymes supporting the reductive and oxidative glutamine metabolism, whereas a reduction in functional HIF1α expression consolidates the inhibition of glycolysis. Finally, in vitro and in vivo experiments document that acidosis accounts for a net increase in tumor sensitivity to inhibitors of SIRT1 and glutaminase GLS1. These findings highlight the influence that tumor acidosis and metabolism exert on each other. Cancer Res; 74(19); 1–13. ©2014 AACR.

“Meeting the doctors and scientists focused on solving the mysteries of cancer has been incredibly inspiring and humbling. My wife and I are already …

“Meeting the doctors and scientists focused on solving the mysteries of cancer has been incredibly inspiring and humbling. My wife and I are already proud Penn alumni, and couldn’t be more pleased to support the university that we both love, and the important work at Penn’s Abramson Cancer Center that has the potential to change the world.” – Jeff Levitt, W’71, Partner in Hope, Chairman and Founder of Precyse Solutions, LLC

Susan and Jeff Levitt, class of ’71

In October 2011, Jeff Levitt came to the Abramson Cancer Center to participate in a very special program – Abundant Treasures and Miraculous Discoveries: Solving the Mysteries of Cancer. Jeff is a member of the Philadelphia chapter of the World Presidents’ Organization (WPO) that partners each year with Penn Medicine to host a program highlighting innovative research and care initiatives. With deep connections to Penn and cancer, it was no mystery that Jeff would find himself attending this program. Jeff and his wife Susan Mazer Levitt attended Penn, both graduating in the Class of 1971, continuing a tradition set by Susan’s father. Their daughter, Kate, is also a proud Penn alumna of the Class of 2002. And Jeff is the Chairman and Founder of Precyse Solutions LLC, a company that is involved in, amongst other things, the gathering and abstracting of clinical data for cancer programs across the country.

Jeff was impressed with the passion and vision of top scientific and clinical faculty as they shared their advances in novel treatments for breast, melanoma, lung, and pancreatic cancers – never shying away from challenging diseases. He knew right away that he wanted to help support their efforts and after hearing from Dr. David Roth, Chair of Penn’s new Center for Personalized Diagnostics (CPD), he settled on a project to be a part of.

“Personalized medicine is today’s science,” says Roth. “Every day I come to work thinking that today might be the day that we discover the genetic breakthrough we’re looking for to cure cancer. Philanthropy helps drive forward our discoveries at an even faster pace, and gives us the resources to explore so many different promising areas of personalized, effective cancer care.”

With the help of Dr. Roth and others, Penn has the infrastructure to analyze a cancer patient’s tumor for the gene, protein or molecule that makes it different. It is the gathering of this information that will allow doctors to understand fully what will help one patient versus another, improving not only outcomes, but also quality of life. For the researchers, scientists and clinical staff at Penn Medicine, it’s personal.

For the Levitts, it’s personal too. Jeff and Susan decided to give both their money and their time to help make a difference at the Abramson Cancer Center. As members of the Abramson Cancer Center Director’s Leadership Council, they are active volunteers and advocates. “We support a multitude of worthy organizations, but it’s been particularly fulfilling to give to Abramson,” shares Susan. Jeff continues, “It’s hard to calculate our return on investment for being part of an institution making such a profound difference in Philadelphia, especially when we read the stories of hope that they provide to so many people suffering from cancer in Philadelphia and around the world.”

Support the Abramson Cancer Center

Penn’s Abramson Cancer Center is a place of healing and inspiration – through innovative research and compassionate care, charitable donations provide hope to patients and families.

Make a gift to the Abramson Cancer Center here, or contact Evelyn Schwartz at [email protected] or (215) 898-8625.

“Meeting the doctors and scientists focused on solving the mysteries of cancer has been incredibly inspiring and humbling. My wife and I are already proud Penn alumni, and couldn’t be more pleased to support the university that we both love, and the important work at Penn’s Abramson Cancer Center that has the potential to change the world.” – Jeff Levitt, W’71, Partner in Hope, Chairman and Founder of Precyse Solutions, LLC

Susan and Jeff Levitt, class of ’71

In October 2011, Jeff Levitt came to the Abramson Cancer Center to participate in a very special program – Abundant Treasures and Miraculous Discoveries: Solving the Mysteries of Cancer. Jeff is a member of the Philadelphia chapter of the World Presidents’ Organization (WPO) that partners each year with Penn Medicine to host a program highlighting innovative research and care initiatives. With deep connections to Penn and cancer, it was no mystery that Jeff would find himself attending this program. Jeff and his wife Susan Mazer Levitt attended Penn, both graduating in the Class of 1971, continuing a tradition set by Susan’s father. Their daughter, Kate, is also a proud Penn alumna of the Class of 2002. And Jeff is the Chairman and Founder of Precyse Solutions LLC, a company that is involved in, amongst other things, the gathering and abstracting of clinical data for cancer programs across the country.

Jeff was impressed with the passion and vision of top scientific and clinical faculty as they shared their advances in novel treatments for breast, melanoma, lung, and pancreatic cancers – never shying away from challenging diseases. He knew right away that he wanted to help support their efforts and after hearing from Dr. David Roth, Chair of Penn’s new Center for Personalized Diagnostics (CPD), he settled on a project to be a part of.

“Personalized medicine is today’s science,” says Roth. “Every day I come to work thinking that today might be the day that we discover the genetic breakthrough we’re looking for to cure cancer. Philanthropy helps drive forward our discoveries at an even faster pace, and gives us the resources to explore so many different promising areas of personalized, effective cancer care.”

With the help of Dr. Roth and others, Penn has the infrastructure to analyze a cancer patient’s tumor for the gene, protein or molecule that makes it different. It is the gathering of this information that will allow doctors to understand fully what will help one patient versus another, improving not only outcomes, but also quality of life. For the researchers, scientists and clinical staff at Penn Medicine, it’s personal.

For the Levitts, it’s personal too. Jeff and Susan decided to give both their money and their time to help make a difference at the Abramson Cancer Center. As members of the Abramson Cancer Center Director’s Leadership Council, they are active volunteers and advocates. “We support a multitude of worthy organizations, but it’s been particularly fulfilling to give to Abramson,” shares Susan. Jeff continues, “It’s hard to calculate our return on investment for being part of an institution making such a profound difference in Philadelphia, especially when we read the stories of hope that they provide to so many people suffering from cancer in Philadelphia and around the world.”

Support the Abramson Cancer Center

Penn’s Abramson Cancer Center is a place of healing and inspiration – through innovative research and compassionate care, charitable donations provide hope to patients and families.

Make a gift to the Abramson Cancer Center here, or contact Evelyn Schwartz at [email protected] or (215) 898-8625.