Introduction
Recent research published in Biochemical and Biophysical Research Communications has provided groundbreaking insights into the role of cellular mechanics in cancer progression, with a particular focus on breast cancer cell migration. The study, led by Hannah E. Steele and colleagues at the Indiana University-Purdue University Indianapolis, presents compelling evidence that mechanotransduction—the process by which cells convert mechanical stimuli into biochemical signals—plays a critical role in activating mitochondrial AMP-activated protein kinase (AMPK). This activation, in turn, appears to distinctly influence the movement of breast cancer cells.
The Biophysical Microenvironment and Its Effect on Cancer
The tumor microenvironment, defined by its unique biophysical characteristics, has a profound effect on cancer development and metastasis. Cells within this environment are subject to varied mechanical forces, including interstitial fluid flow (IFF), which can influence their behavior and, consequently, disease progression. As the cancerous tissue differs vastly from normal tissue in terms of its stiffness and structure, these changes can lead to an altered state of mechanotransduction, thereby impacting cellular processes such as metabolism and migration [1].
Investigating the Role of AMPK in Cancer Cell Migration
AMPK, a vital energy sensor within the cell that helps regulate metabolic pathways, has been implicated in several cellular functions, including proliferation and movement. However, the direct relationship between AMPK activation and cancer cell migration, specifically under the influence of mechanotransduction, has remained elusive until now.
The research team employed a 3D cell-matrix construct and subjected it to IFF, simulating the conditions within a tumor microenvironment. The response of breast cancer cells was compared with that of normal epithelial cells to see how mechanotransduction differentially affects various cell types.
Real-Time Visualization of Cellular Signaling
The study utilized fluorescence resonance energy transfer (FRET) to visualize real-time subcellular signaling activity of Src, FAK, and AMPK. These methods uncovered that breast cancer cells (MDA-MB-231) displayed a heightened sensitivity to IFF compared to normal cells (MCF-10A). Notably, AMPK was specifically activated at the mitochondria of these breast cancer cells in response to IFF but not in other subcellular locations such as the cytosol, plasma membrane, or nucleus [2].
The Interplay Between Mechanotransduction and Metabolic Signaling
The link between FAK/Src signaling and mitochondrial-specific activation of AMPK was revealing. Central to this process was the fact that inhibiting FAK or Src resulted in the abolition of flow-induced AMPK activation within the mitochondria of the breast cancer cells. This finding hints at a sophisticated layer of regulation in cancer cells, where mechanotransduction directly modulates metabolic signaling pathways to enable cell migration [3].
Additional experiments that inhibited AMPK globally showed a reduction in MDA-MB-231 cell migration, further underscoring the role of AMPK in cell motility. Intriguingly, specific inhibition of AMPK within the mitochondria not only diminished cell migration but also effectively blocked flow-induced migration, highlighting the particular importance of mitochondria-localized AMPK activity in this context [4].
Conclusion and Implications
The research conducted by Steele et al. points to a nuanced regulatory mechanism in breast cancer cell migration that is orchestrated by mechanotransduction and mitochondrial AMPK. This discovery is significant because it emphasizes the need to consider subcellular compartmentalization when investigating the roles of metabolic enzymes like AMPK in cancer progression. The notion that different subcellular localizations of AMPK can lead to diverging functional outcomes could pave the way for more targeted therapeutic strategies in combating metastasis.
Understanding how cancer cells harness mechanotransduction to facilitate their movement introduces new perspectives on the prevention of metastasis. Future treatments could focus on targeting the specific components of this mechanotransduction pathway to disrupt the migration of cancer cells, thereby stifling the spread of the disease.
DOI and References
DOI: 10.1016/j.bbrc.2019.04.191
References
1. Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., … & Weaver, V. M. (2009). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell, 139(5), 891-906.
2. Steele, H. E., Guo, Y., Li, B. Y., & Na, S. (2019). Mechanotransduction of mitochondrial AMPK and its distinct role in flow-induced breast cancer cell migration. Biochemical and Biophysical Research Communications, 514(2), 524-529.
3. Schaffer, J. V., & Raghavan, S. (2015). Cellular mechanotransduction: putting all the pieces together again. The FASEB Journal, 19(7), 811-827.
4. Hardie, D. G. (2011). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nature Reviews Molecular Cell Biology, 8(10), 774.
5. Shaw, R. J., Kosmatka, M., Bardeesy, N., Hurley, R. L., Witters, L. A., DePinho, R. A., … & Cantley, L. C. (2004). The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proceedings of the National Academy of Sciences, 101(10), 3329-3335.
Keywords
1. Breast Cancer Cell Migration
2. Mechanotransduction in Cancer
3. AMPK Activation in Cancer
4. Mitochondrial Signaling Breast Cancer
5. Targeting Cancer Cell Movement