Biophysics of cancer

Biophysical techniques—both experimental and computational—play indispensable roles in understanding the physical and biochemical features that distinguish normal cells from cancer cells, and in elucidating effects of mutations on cell signaling events and cell motility that underlie tumor formation, growth, and metastasis. These include mutation-induced changes in the structure, dynamics, or interactions of proteins involved in signal transduction pathways. In this Biophysics of Cancer special issue of Biophysical Journal, 15 outstanding papers highlight progresses in utilizing biophysical concepts and tools to address fundamental questions in cancer biology.

In a review article titled “Cancer as a biophysical disease: Targeting the mechanical-adaptability program,” Nguyen et al. (1) provide an excellent overview, from a biophysicist’s perspective, of how mechanical programs in the cell drive cancer development and metastasis through changes in key cellular processes such as cell division, cell adhesion, metabolism, and motility. The authors also discuss the potential of targeting the mechanical program for therapeutic purposes. In the same vein, two research articles have looked at how variations in internal or environmental mechanical properties differentially impact normal and cancer cells. Malmi-Kakkada et al. (2) used computational modeling of multicellular spheroid growth to predict how intercellular interactions and mechanical pressure regulate cell proliferation, a process critical to tumor formation. A key finding is that the strength of intracellular adhesion, which depends on the location of the cells at the core or periphery of the spheroid, determines the rate of cell division that drives proliferation. Approaching a similar problem from a different perspective, Nikolić et al. (3) wondered about the potential impact of disrupting the ability of cancer cells to adopt multiple mechanical states, which is important for cell survival and migration. Toward this ultimate goal, Brillouin microscopy and broadband frequency optical tweezer microrheology were used to assess intracellular mechanics of cancer cells cultured in two- and three-dimensional environments. Remarkable insights into the diversity of cancer cell’s mechanical states have emerged from the measurements.

Current computational and experimental techniques allow access to biological processes at a wider range of spatiotemporal scales than was previously possible. As an example, Kandy and Radhakrishnan (4) describe a mesoscale model to study changes in the shape of cell membranes induced by membrane-attached crowders such as the glycocalyx and actin networks. Such studies provide insights into the regulation of cell morphology and thereby cellular trafficking. At the nanoscale level, Jabak et al. (5) used single-molecule optical trapping to explore the molecular mechanism of small-molecule binding to DNA in order to gain insights into how chirality affects the binding affinity and kinetics. Two excellent papers (6,7) provide additional examples of computational approaches that can be used to explore various aspects of cancer-related biological phenomena at multiple scales of space and time.

As already noted, biophysical methods play a fundamental role in deciphering changes in the structure and dynamics of biomolecules. These changes often result in altered or attenuated interactions with interaction partners, and altered interaction networks can lead to the development of cancer. This broad topic is the focus of three excellent papers (7, 8, 9) in this issue of Biophysical Journal. Target identification and the development of biomarkers or anticancer therapies are other active areas of interest for many biophysicists. Along these lines, Anne M. Brown and colleagues investigated a potential prognostic marker for an aggressive form of brain cancer, glioblastoma (10). As a foundational work for the future development of therapeutic agents, two papers (8,9) have focused on atomically detailed analyses of the structure and dynamics of cancer-associated proteins (8,9), while a third investigated the molecular mechanism of small-molecule binding to DNA (5).

Enormous effort is currently being directed toward studying a particular anticancer drug target, KRAS. This includes the application of essentially all available biophysical techniques in order to elucidate the structure, dynamics, and interactions of KRAS in isolation and with its partner proteins in solution and membrane environments. These efforts helped usher in the first FDA-approved direct KRAS inhibitor that was marketed in 2021. However, much remains to be learned about this hitherto elusive target whose mutations account for nearly a fifth of all human cancers. Pushing the frontier in this space are four papers that provide new insights into the organization of KRAS on the surface of model membranes alone (11) or in complex with another protein (12), its interaction with a chaperone protein (13), and its dynamics relative to its close homologs NRAS and HRAS (14). These studies are noteworthy not only because of their depth and sophistication but also because of the enormous amount of data they have analyzed. For example, Ngo and Garcia have conducted atomistic molecular dynamics simulations in the millisecond timescale, a feat still only rarely achieved in the field (11). Moreover, the work of Nguyen et al. (12) and Michalak et al. (13) represents an excellent example of how to combine a state-of-the art simulation and spectroscopic techniques, such as NMR and surface plasmon resonance, to obtain richer information than is possible from one or a few techniques alone.

These papers represent only a handful of the many diverse ways by which biophysics advances our understating of cancer in its enormous complexities. Existing and emerging biophysical techniques will no doubt continue to occupy a central role in future efforts to defeat cancer.

Editor: Alemayehu A. Gorfe.