Despite major discoveries in cancer biology in recent years, metastases (spread of primary tumor cells) are the cause of 90% of human cancer deaths. Very little is known about the genetic and biochemical determinants of metastasis. Metastasis is a multistage process involving abnormal tumor cell migration and invasion, transit in the blood or lymph, extravasation and colonization in the normal tissues at secondary sites. Acquisition of invasive behavior involves activation of signaling pathways controlling cytoskeletal dynamics, as well as turnover of cell–matrix and cell–cell adhesions. Cancer invasion is a heterogeneous and adaptive process involving changes in cell morphology and generation of cell polarity. Cancer cells display exceptional ability to adapt to different environmental conditions engaging in different migration strategies. Cancer cells can migrate either individually in the absence of cell–cell junctions, or collectively upon retention of cell–cell adhesions. In turn, cancer cells can use a number of strategies when migrating individually such as they could change their shape between elongated-mesenchymal, rounded- amoeboid, spike-mediated or while migrating collectively they would behave as if in a multicellular streaming or tumor budding to accomplish collective invasion into normal tissues at a different site.
Scaffolding protein known as NEDD9 is a critical regulator of cancer cell migration especially for individual mesenchymal type of migration for many types of tumor cells and its elevated expression has been reported in many tumor types including breast, lung, and melanoma. Mesenchymal migration is characterized by an elongated cell morphology, multiple focal/3D adhesions, and the ability to degrade ECM by matrix metalloproteinases (MMPs) creating a path through the basement membrane/tissue. A major regulator of mesenchymal migration, Rac1 GTPase, is activated by a number of guanine nucleotide exchange factors (GEFs), including melanoma-specific DOCK3, which in turn is recruited/activated by NEDD9.
In a recent study conducted by a former colleague and friend Dr. Elena Pugacheva, an Associate Professor at University of West Virginia, amoeboid movement of triple negative breast cancer (TNBC) cells was found to be defective in some respects such as decreased cell contractility. It is important to note that a triple negative breast cancer diagnosis means that the tumor is estrogen receptor-negative, progesterone receptor-negative and HER2-negative, thus giving rise to the name “triple negative breast cancer.” While this type of breast cancer is typically responsive to chemotherapy, the bad news is when TNBC tumor recurs then it becomes hard to treat as they do not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab) which is commonly used to treat other types of breast cancer in case of tumor recurrence. For doctors and researchers, there is intense interest in finding new medications that can treat this kind of breast cancer.
Dr. Pugacheva and her team at West Virginia University School of Medicine provides a mechanistic explanation as to how NEDD9 drives invasion processes in TNBC cells which paves roads to develop new therapeutic strategies so as to use a combination of anti-NEDD9/AURKA and anti-ROCK–targeting compounds to inhibit these movement signaling cascades relevant in TNBCs. In this study, investigators report that deficiency in NEDD9 signaling itself leads to inhibition of key aspects of both mesenchymal and amoeboid migration in TNBC cells, resulting in substantial hindrance on cell invasion and metastasis. NEDD9 deficiency in TNBC cells results in rounded/amoeboid morphology along with a decrease in the total number of mature (pFAK/pPaxillin positive) adhesions and an increase in the number of recently formed adhesion structures. Together, these findings suggest that NEDD9 is also required for the disassembly of fibrillar adhesions similar to vinculin, which regulates the recruitment and release of focal adhesion proteins in a force-dependent manner. Overall this work strongly suggests that a dual targeting strategy (using both anti-NEDD9/AURKA and anti-ROCK–targeting compounds) could be an efficient therapeutic approach to hinder the metastasis of triple negative breast cancers, indicating towards an important need for further clinical evaluation of this therapeutic regimen to impede the spread of disease and improve patient survival in patients setting.
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