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Scientists at VCU Massey Cancer Center uncovered a previously unrecognized relationship between two sets of proteins that operate in tandem to fend off the growth of pancreatic cancer. The findings could provide pivotal information for the development of novel therapies for what is currently an incurable disease.

Pancreatic ductal adenocarcinoma (PDAC) accounts for the vast majority of all pancreatic tumors and is the fourth-leading cause of cancer-related deaths worldwide. Most patients are diagnosed at an advanced stage when the disease is already inoperable and there are no effective therapies.

New research published in the Journal of Cell Biology, led by Azeddine Atfi, Ph.D., leader of the Cancer Biology research program who holds the Mary Anderson Harrison Distinguished Professorship in Cancer Research at Massey, discovered that the simultaneous activation of two gene-regulating proteins — Prdm16 and Smad4 — is associated with a cutback in pancreatic cancer progression.

Model for the functional interaction between Smad4 and Prdm16 during PDAC formation and progression (illustration published in the Journal of Cell Biology).

“Our study sheds light on a previously uncharacterized interplay between Smad4 and Prdm16, which appears to dictate the growth trajectory of pancreatic cancer, that could ultimately pave the way for innovative therapeutic breakthroughs to curb this deadly disease,” said Atfi, who is also a professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine.

The absence of Smad4 has previously been connected to cancer growth in PDAC cells. Prdm16 controls a variety of essential cellular processes, including the construction of tissues and organs. The protein was first observed scientifically in leukemia, where previous research indicated that it might function as a tumor suppressor, but had not been studied in pancreatic cancer.

Atfi and his research team discovered that when both Prdm16 and Smad4 were inactivated, the pancreatic tumors grew aggressively and formed metastatic lesions in the lung. However, they also determined that when Smad4 was inactivated alone, Prdm16 became overexpressed and contributed to cancer growth.

When the research team observed cells with both proteins activated — where Prdm16 was located downstream along the same genetic messaging pathway as Smad4 — Prdm16 successfully suppressed tumor progression and metastasis in pancreatic cancer cells, suggesting they both play an important, combined role in fighting off cancer cells.

“Think of Smad4 as a movie director telling Prdm16 how to fulfill the role of a cancer fighter. Without Smad4 as the director, Prdm16 starts to play the part of a cancer supporter,” Atfi said. “Our findings point to a previously unidentified mechanism that orchestrates the antitumor role of Prdm16, and further shed new insights into the molecular cause of pancreatic cancer.”

More research needs to be conducted to firmly establish whether Prdm16 elicits anti-tumor activity at early stages, and if this occurs through directs effects on cancer cell growth or through reprogramming of the tumor microenvironment. Atfi said a more comprehensive investigation of how Smad4 and Prdm16 interact could help identify additional genetic players that could be targeted through cancer treatment.

“We anticipate that our discovery will guide forthcoming studies seeking to understand and unravel the cellular paradigms of pancreatic cancer,” Atfi said.

Atfi collaborated on this research with Allyn Austin Bryan, Deanna Campbell, Creighton Friend, Eric Hurwitz, Ting-Xuan Lu, Thien Ly Nguyen, Parash Parajuli, Ph.D., and Steven Smith, M.D., Ph.D., of the VCU School of Medicine; Seval Ozkan and Keli Xu, Ph.D., of the University of Mississippi Medical Center; Celine Prunier of the Sorbonne Université; and Mohammed Razzaque, M.B.B.S., Ph.D., of the Lake Erie College of Osteopathic Medicine.

This research was supported by the National Cancer Institute (R01CA24084, R01CA210911, R01CA251405), the U.S. Department of Defense (PR162051), and, in part, with funding by Massey’s NIH-NCI Cancer Center Support Grant (P30 CA016059).

Written by: Blake Belden