MAP-ping Networks That Control Cell Movement: Implications for Understanding Metastasis

MAP4K4 staining

Staining of the MAP4K4 signaling protein

For many patients with cancer, it is the spread of tumor cells from the original site to another organ or part of the body (a process called metastasis) that presents the biggest challenges associated with their disease. Not only are groups of tumor cells at distant sites difficult to treat, but where and how fast metastases grow can be very unpredictable.

Unfortunately, strategies to treat or prevent metastasis are limited, in large part because the signaling networks in cancer cells and in the microenvironment that drive the spread of cancer cells are poorly understood.

One essential step in the metastatic cascade, whereby cancer cells break away from their neighbors, invade into the surrounding tissue and travel to distant locations, typically through blood or lymph vessels, is cell movement. The molecular machinery that regulates the movement of cells is very tightly regulated so that cells only travel where and when they are programmed. For example, the well-orchestrated coordination of cell movement is required for tissue and organismal development, or for wound healing when tissue architecture is breached.

Xiaoyang Wu, PhD

Xiaoyang Wu, PhD, assistant professor of the Ben May Department for Cancer Research, studies cell movement in normal skin cells in order to better understand how tumor cells hijack the cell movement machinery to acquire the ability to metastasize. In a study published this week in the journal Developmental Cell, Wu and colleagues identify key components of the molecular machinery responsible for cell movement, particularly steps involving the detachment of cells from their surrounding extracellular matrix. This matrix acts like a scaffold upon which the cells travel, and the extent of cell movement is dictated by how strong the points of attachment (also known as focal adhesions) from the cell to the matrix are.

Using large-scale approaches to identify proteins involved in focal adhesion turnover, Wu’s team identified a signaling protein named mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) as a major regulator of focal adhesion disassembly. They found that MAP4K4 associates with the intracellular microtubule cytoskeleton, specifically by binding to the EB2 microtubule-binding protein and IQSEC1, a guanine nucleotide exchange factor responsible for activating Arf6.

Arf6 is a signaling protein that is known to regulate intracellular protein trafficking and remodel the cytoskeleton, and, as shown in this work, can promote internalization of the matrix receptors found in focal adhesions. As proof for MAP4K4 action in cell movement, skin cells in mice engineered to lack MAP4K4 had stabilized focal adhesions and were unable to migrate normally.

Although these findings don’t directly address the role of the MAP4K-EB2-IQSEC1-Arf6 signaling network in tumor cell movement and metastasis, these questions are the focus of some of Wu’s current and future work.

Wu has been funded by the American Cancer Society to study a protein called RIPK4 in skin cancer stem cells in order to develop new therapeutic approaches to skin cancer. In addition to funding from the V Foundation for Cancer Research and the Cancer Research Foundation, he was recently awarded his first R01 peer-reviewed research grant from the National Institutes of Health to dissect how cytoskeletal dynamics regulate key developmental signaling in skin stem cells.

About Kathleen Goss (30 Articles)
Kathleen Goss, PhD, is the Director for Strategic Partnerships and senior science writer at the University of Chicago Medicine Comprehensive Cancer Center.
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