Despite the availability of effective treatment to combat the early stages of the disease, breast cancer remains one of the deadliest forms of cancer in women. This is due to the aggressive nature of the invasive stage of the disease, the transition to which is still not fully understood.
To better understand this switch, researchers from the University of Turku and Åbo Akademi University investigated the action of associated proteins, discovering a dual role of the filopodia-inducing protein myosin-X (MYO-10). This protein was once thought to contribute solely to the progression of the disease – the work of the InFLAMES group (published in Developmental Cell) has challenged this understanding and shown that MYO-10-induced filopodia play a role as a protective entity in the initial stages of breast cancer.
Ductal carcinoma in-situ (DCIS) is a pre-invasive stage of breast cancer characterised by tumour cells that are surrounded by a protective barrier known as the basement membrane – a sheet-like extracellular matrix structure. A breach of this barrier can cause cancer cells to invade the surrounding tissue, dramatically decreasing survival rates.
The transition from early-stage to aggressive and invasive cancers is partly facilitated by filopodia – finger-like entities comprised of actin that play a variety of roles in normal developing cells, including promoting angiogenesis and wound healing. However, these protrusions can be the agents of far more sinister processes – encouraging metastasis and cancer-cell survival and facilitating invasion of the surrounding stroma through interaction with the basement membrane. The protein myosin-X (MYO-10) is a known inducer of filopodia and has previously been found in elevated amounts in invasive breast cancer samples. This correlation between severe disease and increased MYO-10 levels led the Finnish researchers to investigate the role of the protein and associated filopodia in DCIS, as well as the transition between the two stages.
A two-handed approach
The InFLAMES group used RNA in-situ hybridisation and immunostaining to confirm the increased levels of the protein compared to that found in healthy breast tissue, finding increased MYO-10 in the edges of tumours, especially in invasive samples. This supported the established idea that the protein and its associated filopodia contribute to progression.
Shockingly, however, when the researchers depleted MYO-10 levels using RNAi in DCIS xenograft models, the protective cells in the basement membrane were compromised. The model of DCIS transformed into something much more reminiscent of invasive cancer, with a lack of distinct borders and increased cancer cell migration.
The depletion of MYO-10 levels decreased the abundance and size of filopodia, and the affected xenografts were seen to be even more invasive than those with elevated MYO-10 levels. The team observed that filopodia recruited fibronectin to the extracellular matrix, contributing to the integrity of the basement membrane.
This confusing result led the researchers to conclude that MYO-10, and consequently the MYO-10-induced filopodia, play two distinct roles in cancer progression; initially as a protective entity, preventing cancer cell migration and stabilising the basement membrane, before switching in the latter stages of disease to facilitate dispersal of cancer cells.
Figure 1: Graphical abstract showing the results of the study and the dual-role of MYO-10. The protective role of MYO-10 is pictured on the left side of the figure, with the pro-invasive stage described on the right. The lower centre image demonstrates the compromised basement membrane in a MYO-10 depleted tumour.
More questions than answers?
Whilst the results, described by Professor Johanna Ivaska as “very surprising”, don’t answer every question surrounding the role of MYO-10 and filopodia in cancer, they certainly bring about new challenges. Those investigating potential treatments for breast cancer are faced with a new hurdle – previous ideas that MYO-10 and filopodia could be used as drug targets are now called into question, with a caution issued by Dr. Guillaume Jacquemet that intervention of this nature “could actually make things worse.”