Novel targeted agents, either alone or in combination with cytotoxic agents, may result in superior treatment for patients.

Cutaneous metastasis of an occult malignancy to the umbilicus has come to be known as a Sister Mary Joseph's nodule (SMJN). More than 400 cases of this well-described clinical presentation of advanced gastrointestinal and gynecologic cancers have been reported. Pancreatic cancer presenting as a SMJN is a rare phenomenon. In most series, the pancreas is the source of a SMJN in 7% to 9% of cases. We report a case of pancreatic adenocarcinoma in which the initial presenting sign was a SMJN. We also reviewed the published literature from the last 100 years on this phenomenon by conducting a detailed PubMed search. Including this case, we identified 57 cases of SMJN originating from the pancreas. The clinical patient characteristics with regard to age, male-female ratio, race, and prognosis of these cases were similar to that of pancreatic cancer in general. In contrast, 91% of these cases originated in the tail and body of the pancreas rather than the head of the pancreas. This case emphasizes that pancreatic cancer should be considered in the differential diagnosis of umbilical metastasis.

Lysophosphatidic acid acyltransferase (LPAAT-β) is a phosphatidic acid (PA) generating enzyme that plays an essential role in triglyceride synthesis. However, LPAAT-β is now being studied as an important regulator of cell growth and differentiation and as a potential therapeutic target in cancer since PA is necessary for the activity of key proteins such as Raf, PKC-ζ and mTOR. In this report we determine the effect of LPAAT-β silencing with siRNA in pancreatic adenocarcinoma cell lines. We show for the first time that LPAAT-β knockdown inhibits proliferation and anchorage-independent growth of pancreatic cancer cells. This is associated with inhibition of signaling by mTOR as determined by levels of mTORC1- and mTORC2-specific phosphorylation sites on 4E-BP1, S6K and Akt. Since PA regulates the activity of mTOR by modulating its binding to FKBP38, we explored the possibility that LPAAT-β might regulate mTOR by affecting its association with FKBP38. Coimmunoprecipitation studies of FKBP38 with mTOR show increased levels of FKBP38 associated with mTOR when LPAAT-β protein levels are knocked down. Furthermore, depletion of LPAAT-β results in increased Lipin 1 nuclear localization which is associated with increased nuclear eccentricity, a nuclear shape change that is dependent on mTOR, further confirming the ability of LPAAT-β to regulate mTOR function. Our results provide support for the hypothesis that PA generated by LPAAT-β regulates mTOR signaling. We discuss the implications of these findings for using LPAAT-β as a therapeutic target.

No abstract