Cell Membrane Sorcery: Unlocking Cancer’s Rampage

Every cell is encased by a lipid bilayer, a structure that not only confers shape but also establishes a boundary between the cellular interior and its external milieu. However, emerging scientific insights suggest that these cellular envelopes perform functions extending beyond mere containment; they also exert influence over the activity of protein receptors embedded within them.

A recent investigation undertaken by chemists at the Massachusetts Institute of Technology (MIT) further substantiates this concept. This research team deduced that modifications to the composition of the cell membrane can correspondingly alter the functionality of a membrane receptor implicated in the promotion of cellular proliferation.

It has been identified that the Epidermal Growth Factor Receptor (EGFR) can become constitutively active when the cell membrane exhibits an abnormally high prevalence of lipids bearing a negative charge, according to the scientists’ findings. This phenomenon may offer an explanation for the heightened state of proliferation observed in cancerous cells characterized by elevated levels of these specific lipids, enabling their unchecked division.

The long-held belief regarding the function of a membrane was that it served merely as a structural framework, an organizational matrix. Nevertheless, a growing body of observations indicates that perhaps these membrane lipids are, in fact, actively participating in receptor function.” 

Gabriela Schlau-Cohen, Professor of Chemistry at MIT and the study’s senior author

These discoveries illuminate the potential for developing novel therapeutic strategies targeting tumors. Such approaches could involve neutralizing the negative charge within the membrane, which might serve to attenuate EGFR signaling, she elaborated.

Shwetha Srinivasan, who earned her PhD from MIT in 2022, is the principal author of the paper, which has been published in the esteemed journal *eLife*. The collaborative research effort also included contributions from former MIT postdoctoral fellows Xingcheng Lin and Raju Regmi, Xuyan Chen (PhD ’25), and Bin Zhang, an Associate Professor of Chemistry at MIT.

Receptor dynamics

The EGF receptor, situated on cells lining the body’s surfaces and internal organs, is one of numerous receptors crucial for regulating cell growth. Certain forms of cancer, notably lung cancer and glioblastoma, exhibit overexpression of the EGF receptor, a condition that can precipitate uncontrolled cellular proliferation.

Consistent with the majority of receptor proteins, EGFR traverses the entirety of the cell membrane. Historically, elucidating the mechanisms by which signals are transmitted across the entire receptor has presented significant challenges, primarily due to the inherent difficulty in constructing membranes with correctly oriented, full-length transmembrane proteins and subsequently examining both extremities of these proteins.

To facilitate the investigation of these signaling pathways, Professor Schlau-Cohen’s laboratory employs nanodiscs, a distinctive class of self-assembling membrane structures designed to replicate the characteristics of a cellular membrane. Within these nanodiscs, researchers can successfully integrate receptors, thereby enabling the team to scrutinize the functionality of intact, full-length receptors.

Through the application of a technique known as single-molecule FRET (fluorescence resonance energy transfer), the researchers are equipped to observe alterations in the receptor’s conformation under varying environmental conditions. Single-molecule FRET allows for the precise measurement of distances between disparate segments of the protein by affixing fluorescent labels and subsequently quantifying the rate of energy transfer between these labels.

In prior investigations, Professor Schlau-Cohen and Professor Zhang utilized single-molecule FRET alongside molecular dynamics simulations to delineate the events occurring upon the binding of EGFR to EGF. Their findings revealed that this molecular interaction induces a conformational change in the transmembrane domain of the receptor, and this structural alteration subsequently activates the intracellular portion of the receptor, initiating cellular mechanisms that stimulate growth.

Stuck in an overactive state

In the course of their recent study, the researchers adopted a comparable methodology to examine the impact of modifying membrane composition on receptor function. Initially, they investigated the effects of elevated concentrations of negatively charged lipids on the cell membrane and EGFR activity.

Under normal physiological conditions, approximately 15 percent of the cell membrane consists of negatively charged lipids. The research team observed that membranes with negatively charged lipid content ranging from 15 to 30 percent functioned as expected. However, when this proportion escalated to 60 percent, the EGFR receptor became irreversibly locked in an activated conformation.

In this persistently active state, the signaling pathway that drives growth remains continuously engaged, irrespective of whether EGF is bound to the receptor. A significant number of cancerous cells display augmented levels of these lipids, and this mechanistic insight may shed light on the capacity of these cells to proliferate without constraint, according to Professor Schlau-Cohen.

“When the membrane contains elevated quantities of negatively charged lipids, it perpetually maintains an open conformation. The binding or absence of ligand becomes inconsequential,” she stated. “It consistently adopts the conformation that signals the cell to grow, rather than being dependent on EGF binding.”

The research group also leveraged this experimental system to probe the role of cholesterol in EGFR functionality. Upon constructing nanodiscs with augmented cholesterol levels, the researchers discovered that the membranes exhibited increased rigidity. This enhanced rigidity, in turn, was found to suppress EGFR signaling.

Financial support for this research was provided by the National Institutes of Health and MIT’s Department of Chemistry.