Pituitary tumor cells are reprogrammed to an aggressive state following prenatal alcohol exposure through the overexpression of DPPA4 via the epigenetic modification. DPPA4 alters tumor microenvironment through Wnt/β-catenin signaling that enhances the aggressive nature of tumor cell and making them uncontrollable. DPPA4 and its modifiers can be potential therapeutics for aggressive tumors. Graphic: Ujjal Das, Ph.D. from Sarkar Lab.
Dipak Sarkar, Distinguished Professor of Animal Sciences, and his team recently published the manuscript, “DPPA4 increases aggressiveness of pituitary neuroendocrine tumors by enhancing cell stemness,” in the journal, Neurooncology. One of the leading oncology publications in the world, the journal has a high reputation in the field and is ranked number 15 of 322 international oncology journals with an impact factor of 16.4.
Distinguished Professor Dipak Sarkar. Photo credit: Rutgers University.
In this publication, Sarkar and team demonstrate the possible role of a developmental pluripotency-associated4 (DPPA4) gene in adult aggressive pituitary neuroendocrine tumors (PitNETs). These tumors are common intracranial tumors that can be hormone-secreting and are an important cause of decreased gonadal functions and infertility in humans. Some of these tumors are insensitive to therapy and exhibit aggressive behavior, characterized by gross invasion of the surrounding tissues or distance metastasis. As a result, the management of aggressive PitNET is a challenge because of the unexplained cause of this disease.
Using both aggressive PitNETs of fetal alcohol exposed rats and of human patients, Sarkar’s team has shown that these tumors overexpress the DPPA4 gene that led to increased production of tumor stemness factors known to be responsible for uncontrolled growth.
Also, DPPA4 effects on tumor aggressiveness is mediated by Wnt/β-catenin signaling. DPPA4 is one of the embryonic stem cell transcription factors known to regulate the genetic machinery of the embryonic development but has never been connected to the increased tumor cell stemness and aggressiveness in adult tumors.
Sarkar’s laboratory also showed that DPPA4 is overexpressed following alcohol exposures due to epigenetic modification of this gene. Their study also presented evidence of a causative role of DPPA4 in alcohol promotion of cancer.
According to Sarkar, their data identify an oncogenic role of DPPA4 in the pituitary and show a direct link between an expanded stem cell niche within the tumor microenvironment with tumor aggressiveness. In addition, the data identifies potential therapeutic uses of DPPA4 gene expression/action modifiers in the treatment of aggressive PitNETs.
Because DPPA4 was also found previously to be highly expressed in non‑small‑cell lung cancer tissues, this cell stemness regulator may also be involved in the development and progression of other cancers.
Members of Sarkar team involved in this work are postdoctoral fellows Ujjal Das, Shaista Chaudhary and Bénédicte Rousseau; graduate student Shaima Jabbar; research associate Omkaram Gangisetty, Ph.D., and neurosurgeon Simon Hanft, M.D.
