Coping with stress to survive: pancreatic cancer cells rely on MYRF.

Pancreatic cancer is characterized by extreme heterogeneity, with well differentiated and poorly differentiated cells coexisting within the same tumor mass in the majority of patients. Low-grade tumors (namely tumors that appear normal at a first histological analysis and tend to grow and spread more slowly than high-grade tumors) are mostly constituted by well differentiated secretory cells and low numbers of poorly differentiated cells, whereas high-grade tumors are made up mainly by poorly differentiated cells, with a smaller proportion of well differentiated cells. In spite of the implications that such a heterogeneity may have for responsiveness to treatment, the underlying molecular bases are unknown.

Both normal and cancer cells with high secretory activity must cope with the endoplasmic reticulum (ER) stress caused by protein overload (ER is an organelle of the cell involved in synthesis, folding, modification, and transport of proteins). Although this represents a serious issue for any secretory cell, it is especially critical for tumors, where the ER is already under significant stress due to the increased protein biosynthetic activity triggered by some oncogenes, which results into a higher “workload” for the ER.

Thus, the ability of cancer cells to adapt in order to handle ER stress is critical to survive, grow and metastasize. The identification of the factors involved and the underlying mechanisms enabling the adaptation to ER stress required to survive may offer potential novel targets to halt disease progression.

In a recent paper, the authors show that the transcription factor MYRF is almost exclusively expressed in low-grade, well differentiated pancreatic tumor cells and is essential for their viability. MYRF differential expression in well differentiated vs poorly differentiated pancreatic cancers was found to be directly controlled by HNF1B, a transcription factor that maintains differentiation both in normal pancreas and in pancreatic tumor cells.

How does MYRF contribute to cells’ ability to cope with ER stress? MYRF is associated with the ER membrane; the binding to other MYRF proteins, making up a trimer, triggers the self-cleavage and the release from the membrane. Then, it translocate to the nucleus and binds specific, known sites on chromatin. MYRF binding to chromatin regulates the expression of some genes downstream: so basically when MYRF is expressed it regulates the expression of genes contributing to control and resolve ER stress. Conversely, cells not expressing MYRF cannot control the expression of these genes and are not able to adapt and resolve ER stress, being thus unable to survive and proliferate. Unexpectedly, when tumor cell lines not expressing MYRF were transplanted in mice, tumors appeared larger. However the higher tumor size was due to the accumulation of secretory protein aggregates rather than to increased cell proliferation.

How is ER functioning affected by MYRF expression? In cells lacking MYRF, ER morphology looked deeply altered, and typical signs of ER stress were observed (such as autophagic bodies and lysosomes, which are produced as a cell’s attempt to alleviate the consequences of ER stress); when ER stress was experimentally induced (by treating cells with thapsigargin), ER stress was worsened by the lack of MYRF. On the other hand, MYRF overexpression in contexts where is not normally present allows the cells to gain the ability to adapt and cope with ER stress.

In conclusion, MYRF contributes to attenuate ER stress; by supporting cell adaptation to ER stress, it ultimately enables pancreatic cancer cell survival and growth. Adaptation to ER stress equips cancer cells to front hostile situations commonly encountered during cancer progression, such as hypoxia and nutrient shortage, and hampers anti-tumor immune response. Therefore, drugs interfering with MYRF functioning may render cancer cells vulnerable, preventing cell adaptation to ER stress and making them unable to survive.

Reference. Pancreatic Cancer Cells Require the Transcription Factor MYRF to Maintain ER Homeostasis. Milan, Balestrieri, Alfarano, Polletti, Prosperini, Nicoli, Spaggiari, Zerbi, Cirulli, Diaferia and Natoli. Developmental Cell 2020.