Myoferlin: A skeletal muscle protein with unusual function in pancreatic cancer

Significance 

Cancer starts with mutations in a cell’s DNA, but new University of California San Francisco research shows that the endurance of a tumor relies on its ability to rapidly evolve and adapt to challenges brought about by the environment in which it grows. A major obstacle cancer cells must overcome is their incessant need for more nutrients to fuel their accelerated growth.

Pancreatic ductal adenocarcinoma is an aggressive cancer that took the lives of 47,000 other Americans last year. One hallmark of the Pancreatic ductal adenocarcinoma cells studies is that they grow and divide more quickly than normal cells. This rapid growth is tied to their increased ability to scavenge nutrients wherever possible. Some of these nutrients are processed within cell structures lysosomes—bubble-shaped organelles that are bound by a membrane and hold enzymes tasked with digesting and recycling these nutrients. The authors were particularly interested in the lysosomes of PDA cells because they function at heightened capacity and help process the larger quantities of the fuel necessary to spur cancer cell growth. In doing so, PDA lysosomes must also have specialized safety mechanisms in place to ensure that their increased workload doesn’t lead to excessive damage.

In a new research paper published in Nature Cell Biology, the researchers cultured cancerous and non-cancerous human pancreatic cells, extracted the lysosomes, and determined which proteins were unique to cancer lysosomes. The authors were surprised to find that a protein called myoferlin, which isn’t normally found in pancreatic cells, was plentiful in the cancerous lysosomes. Myoferlin typically only appears on the surface of skeletal muscle cells, where it helps them weather mechanical stress. In pancreatic cancer cells, , Myoferlin seems to strengthen the lysosomal membrane so that it can withstand some bulging without tearing open, said Rushika M. Perera, Ph.D., assistant professor of anatomy in the School of Medicine, who studies metabolic pathways in a cancer known as pancreatic ductal adenocarcinoma. The pancreatic  cancer cells are essentially hijacking a protein that’s usually only used by skeletal muscle cells and then they direct the protein not to the cell surface, where it’s found in muscle cells, but onto the lysosomal membrane, where it’s needed. It’s not clear what triggers the cancerous cells to produce myoferlin but the protein seems to be essential for their survival. When  the authors removed myoferlin from the lysosomal membrane in PDA cells, the organelles broke down, leading to cell death.

Given the lack of treatments and poor prognosis for pancreatic cancer patients (survival is less than 10 months after diagnosis),  There is an urgency to understand the biology of the cancer in more detail in order to design new targeted drugs. Her next steps are to sort out how myoferlin gets directed to the lysosomal membrane and the mechanics of how it prevents the membrane from tearing under stress.

The findings illustrate the importance of looking at such adaptations when considering approaches to reining in cancer, it is important to develop new strategies that cancer cells use to protect their organelles and cell function. Incorporating myoferlin into the membranes of lysosomes is only one way that cancer cells can adapt and keep themselves going. The research work opens the door to understanding the phenomenal array of mechanisms that diseased cells can use to protect themselves, many of which still haven’t yet discovered.

Myoferlin: A skeletal muscle protein with unusual function in pancreatic cancer - Medicine Innovates

About the author

Rushika Perera, Ph.D.
Associate Professor in Medicine
Department of Anatomy
Department of Pathology
Helen Diller Family Comprehensive Cancer Center

Rushika  received her PhD degree from the University of Melbourne and the Ludwig Institute for Cancer Research studying EGFR signaling in Glioblastoma. She conducted studies at Yale University in the laboratories of Derek Toomre and Pietro De Camilli in the department of Cell Biology. Here she used live cell microscopy techniques to determine the topography and dynamics of endocytic vesicular trafficking. She later completed postdoctoral training at Massachusetts General Hospital Cancer Center/Harvard Medical School in the laboratory of Nabeel Bardeesy where she uncovered mechanisms for increased lysosome biogenesis and function in pancreatic cancer.

Reference

Suprit Gupta, Julian Yano, Vincent Mercier, Htet Htwe Htwe, Hijai R. Shin, Gilles Rademaker, Zeynep Cakir, Thomas Ituarte, Kwun W. Wen, Grace E. Kim, Roberto Zoncu, Aurélien Roux, David W. Dawson & Rushika M. Perera. Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth. Nature Cell Biology volume 23, pages232–242 (2021)

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