Researchers Discover How Cell Membrane Composition Drives Cancer Proliferation

Cells are enveloped by a lipid membrane that gives them building and provides a obstruction betwixt nan compartment and its environment. However, grounds has precocious emerged suggesting that these membranes do much than simply supply protection - they besides power nan behaviour of nan macromolecule receptors embedded successful them.

A caller study from MIT chemists adds further support to that idea. The researchers recovered that changing nan creation of nan compartment membrane tin change nan usability of a membrane receptor that promotes proliferation.

Epidermal maturation facet receptor (EGFR) tin beryllium locked into an overactive authorities erstwhile nan compartment membrane has a higher than normal attraction of negatively charged lipids, nan researchers found. This whitethorn thief to explicate why crab cells pinch precocious levels of those lipids participate a highly proliferative authorities that allows them to disagreement uncontrollably.

The longstanding dogma of what a membrane does is that it's conscionable a scaffold, an organizational structure. However, location person been expanding observations that propose that possibly these membrane lipids are really playing a domiciled successful receptor function." 

Gabriela Schlau-Cohen, nan Robert T. Haslam and Bradley Dewey Professor of Chemistry astatine MIT and nan elder writer of nan study

The findings unfastened up nan anticipation of discovering caller ways to dainty tumors by neutralizing nan antagonistic charge, which mightiness move down EGFR signaling, she adds.

Shwetha Srinivasan PhD '22 is nan lead writer of nan paper, which appears successful nan diary eLife. Other authors see erstwhile MIT postdocs Xingcheng Lin and Raju Regmi, Xuyan Chen PhD '25, and Bin Zhang, an subordinate professor of chemistry astatine MIT.

Receptor dynamics

The EGF receptor, which is recovered connected cells that statement assemblage surfaces and organs, is 1 of galore receptors that thief power compartment growth. Some types of cancer, particularly lung crab and glioblastoma, overexpress nan EGF receptor, which tin lead to uncontrolled growth.

Like astir receptor proteins, EGFR spans nan full compartment membrane. Until recently, it has been challenging to study really signals are conveyed crossed nan full receptor, because of nan trouble of creating membranes that person proteins going each nan measurement done them and past studying some ends of those proteins.

To make it easier to study these signaling processes, Schlau-Cohen's laboratory uses nanodiscs, a typical type of self-assembling membrane that mimics nan compartment membrane. When making these discs, nan researchers tin embed receptors successful them, allowing nan squad to study nan usability of nan full-length receptor.

Using a method called azygous molecule FRET (fluorescence resonance power transfer), nan researchers tin study really nan style of nan receptor changes nether different conditions. Single molecule FRET allows them to measurement nan region betwixt different parts of nan macromolecule by labeling them pinch fluorescent tags and past measuring really accelerated power travels betwixt nan tags.

In erstwhile work, Schlau-Cohen and Zhang utilized azygous molecule FRET and molecular dynamics simulations to uncover what happens erstwhile EGFR binds to EGF. They recovered that this binding causes nan transmembrane conception of nan receptor to alteration shape, and that shape-shift triggers nan conception of nan receptor that extends wrong nan compartment to activate cellular machinery that stimulates growth.

Stuck successful an overactive state

In nan caller study, nan researchers utilized a akin attack to analyse really altering nan creation of nan membrane affects nan usability of nan receptor. First, they explored really elevated levels of negatively charged lipids would impact nan compartment membrane and EGFR function.

Normally, astir 15 percent of nan compartment membrane is made up of negatively charged lipids. The researchers recovered that membranes pinch negatively charged lipids successful nan scope of 15 to 30 percent behaved normally, but if that level reached 60 percent, past nan EGFR receptor would go locked into an progressive state.

In that state, nan pro-growth signaling pathway is turned connected each nan time, moreover erstwhile nary EGF is bound to nan receptor. Many crab cells show accrued levels of these lipids, and this system could thief to explicate why those cells are capable to turn unchecked, Schlau-Cohen says.

"If nan membrane has precocious levels of negatively charged lipids, past it's ever successful that unfastened conformation. It doesn't matter if ligand is bound aliases unbound," she says. "It's ever successful nan conformation that's telling nan compartment to grow, not conscionable erstwhile EGF binds."

The researchers besides utilized this strategy to research nan domiciled of cholesterin successful EGFR function. When nan researchers created nanodiscs pinch elevated cholesterin levels, they recovered that nan membranes became much rigid, and this rigidity suppressed EGFR signaling.

The investigation was funded by nan National Institutes of Health and MIT's Department of Chemistry.