BY ALEXANDRA BELAYEW, MONS, BELGIUM
DUX4, the gene that plays a key role in facioscapulohumeral muscular dystrophy (FSHD), is gaining unexpected notoriety in cancer research. According to a recent study1 from the Fred Hutchinson Cancer Research Center in Seattle, Washington, gene mutations in tumor cells can cause a re-expression of DUX4 in malignant tissues. What’s more, DUX4 expression in cancer cells helps them to escape detection by the immune system and proliferate.
Why does this matter? Cells of our immune system patrol all over our body to detect and destroy foreign invaders and abnormal cells, including cancer. In this process, the cancer cell presents its ID with proteins on its surface, and T cells of the immune system recognize and kill it. However, some cancer cells manage to hide their ID from the immune system and can thus develop larger tumors.
Novel immunotherapy drugs are being developed with the aim of “waking up” the patient’s immune cells and driving them to kill cancer cells. Some patients’ tumors shrink very well with such drugs, but unfortunately, after one or two years, some cancers don’t respond to these drugs anymore, because their cells have acquired new tricks that enable them to hide their ID from the immune cells. The Seattle team has found that reactivation of the (normally silent) DUX4 gene was one of those hiding tricks, and was frequently used in many different cancer types.
For researchers in the FSHD field, this new report is very intriguing.2 We know that DUX4 expression is toxic to adult skeletal muscle. We know that DUX4 also is important in normal development when the gene is expressed in the two-cell embryo, where it is active briefly and then shuts off. Now comes this finding that DUX4 has a very different impact on cancer cells – by helping them hide from immune cells.
The research strategy of the Seattle team was the following:
1) knowing that cancer cells often reactivate genes normally only active in early embryos or testis, the authors searched in about 10,000 samples for all the genes that were activated in 33 different cancer types as well as in early embryo or testis, but not in other normal healthy tissues. Among the genes they identified, DUX4 was the most frequently activated in cancers of 22 different organs (including breast, lung, and testis).
2) The authors then characterized the DUX4 mRNA produced in these cancer cells and found it contained all the instructions to express the full DUX4 protein.
3) Cancer cells can present hundreds of different mutations. Chew et. al searched for mutations that could help activate DUX4 gene expression in cancer. They found the DUX4 gene had the polyA addition signal to stabilize the DUX4 mRNA like in FSHD muscles; they detected inactivating mutations in 12 known repressors of DUX4 gene expression, and identified mutations in a new potent repressor named PRPF8 that could be of interest for therapeutic strategies to suppress DUX4 (both in cancer and in FSHD).
4) Cancer cells that expressed DUX4 presented reduced activity of many genes involved in immune function. Moreover, these tumors were less infiltrated by various cells of the immune system, and these produced very low amounts of peptides causing cell death, showing these cancer cells were mostly escaping the immune system.
5) A key step in the recognition of cancer cells by cytotoxic T cells of the immune system is that cancer cells present specific proteins on their surface that belong to a family named MHC Class I. DUX4 was found to prevent expression of these proteins, by blocking the signal (named interferon gamma) that triggers their expression in cancer cells.
6) Finally, a comparison of cancer cells from patients who either responded well or had become resistant to an immunotherapy drug, indicated DUX4 expression was associated with resistance. This observation suggested that DUX4 or its target gene expression could constitute a new biomarker of cancer resistance to immunotherapy. Moreover, drugs inhibiting DUX4 expression could be of interest for cancer immunotherapy as they are for FSHD.
What does this mean for the FSHD community?
Here are several questions that point to some implications of this news:
Is there a link between FSHD and risk of cancer? Increased cancer incidence has not been reported in FSHD, and there are no data to suggest that individuals with FSHD are at higher risk for developing cancers. However, this concern is a reason to evaluate FSHD registries, such as the US National Registry, which have collected health data on FSHD patients and can be periodically analyzed to identify emerging evidence for altered incidence of any specific associated health event.
Could this line of research be beneficial for FSHD? Possibly. Most pharmaceutical companies have very active programs to develop better treatments for cancer. The link between DUX4 and recurring solid tumors will undoubtedly generate interest and lead to additional research funding in this area. These activities may ultimately lead to a cancer therapy targeting DUX4 that could then be adapted for FSHD. More specifically, PRPF8, a novel repressor of the DUX4 gene that was identified in this study, could constitute a new drug target.
Could any of the pending FSHD treatments in development also serve to treat recurring forms of cancer? Possibly. Treatments specifically designed to lower DUX4 in FSHD may have beneficial effects in recurring cancers. It is worth mentioning that a number of cancer drugs are now being investigated as potential FSHD therapies. These oncology drugs may need to be reexamined in the context of DUX4-expressing tumors.
In addition, new studies could investigate why DUX4 expression doesn’t kill cancer cells, while it does cause cell death in FSHD muscle. This would identify a protection mechanism that might be of interest in FSHD treatment.
- Chew G-L et al. DUX4 Suppresses MHC Class I to Promote Cancer Immune Evasion and Resistance to Checkpoint Blockade. Developmental Cell. 50:1-14.
- Himeda CL, Jones P. The Good, the Bad, and the Unexpected: Roles of DUX4 in Health and Disease. Developmental Cell. 2019;50:525-526.