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Cancer Cells’ Shapeshifting Ability Reveals New Drug Targets

Enhanced scanning electron microscopy (SEM) image of cancer malignant cells with high magnification of the cells surface
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Cancer cells can change shape to adapt to new surroundings enabling them to spread throughout the body and evade treatment. Scientists have now discovered how skin cancer cells shapeshift based on their environment and identified two genes that control how the cells change shape. The discovery of these genes offers two potential drug targets to stop melanoma cancer from metastasizing.

The study is published in the journal Cell Reports.

The shape of cancer in 3D

Through years of evolution, cells have learned distinct ways to move throughout the body. This ability is essential in physiological processes such as wound healing, where specific migration programs are executed when required. In the case of cancer cells, however, those migration programs allow the cells to sustain their invasion into tissue.

“We’ve known for a long time that cancer cells can shapeshift to traverse around the body into different tissue types. For example, cells become rounder to go into the blood, if they go into the bone the cells can make drill-like extensions and protrusions to drill through hard tissue. That process of metastasis is dependent on these shape changes. It's when cancer cells metastasize that it becomes lethal for the patient,” Chris Bakal, professor of cancer morphodynamics at The Institute of Cancer Research, told Technology Networks.

One study published in 2019 found that for solid tumors, 66.7% of cancer deaths were registered with metastases as a contributing cause. This figure was founded on population‐based data from the Cancer Registry of Norway for the years 2005‒2015.

Complex and highly coordinated changes in morphology occur during cancer cell metastasis. However, until now, it was unclear how cancer cells determined their shape in response to 3D geometric and mechanical cues.

To explore how cells detect their environment and therefore know which shape to choose, scientists at the Institute of Cancer Research in collaboration with researchers at Imperial College London developed a novel system to study cells in 3D.

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Previous research had focused on studying cells on hard 2D plastic surfaces. By taking 3D images of the cells the researchers were able to get a better understanding of how the cells might behave in a 3D environment.

The scientists used stage-scanning oblique plane microscopy (ssOPM) to take 3D images of the melanoma cells either stuck to a flat and rigid surface or embedded within a 3D soft collagen hydrogel.

The application of ssOPM to study thousands of cells in 3D opens up avenues for future studies to address a wide range of questions in cancer biology. “Most researchers have steered away from 3D imaging in the past because it has typically been a lot slower and more complicated than 2D imaging. However, this new microscope that we have built is one of the fastest 3D microscopes available and allows us to rapidly image a lot of cells in 3D,” said Bakal.

“These microscopes allow us to get a better sense of what these cancer cells look like as three-dimensional objects in tissues that more closely mimic those of the human body.”

Genes control the shapeshifting ability of cancer cells

By quantifying the 3D shape of over 60,000 melanoma cells when certain genes were “switched off” the researchers identified that two genes, TIAM2 and FARP1, as key to the cells' ability to change shape in response to their environment.

The study showed that TIAM2 contributes to shape determination independent of the environment whereas FARP1 regulates shape in ways dependent on the microenvironment. The researchers concluded that changes in cancer cell shape occur in both an environmentally dependent and independent fashion.

The researchers believe these shape-controlling genes could be targeted to prevent melanoma cancer from changing shape and metastasizing. “If we can turn off the genes that are responsible for shape changing in cancer cells we might be able to prevent metastasis completely. This would be an entirely new way of preventing cancer cells from spreading,” said Bakal.

These genes have been identified as good candidates for drug discovery due to their similar structure to other proteins for which drugs are already in preclinical development. “By looking at the 3D shape of cells as they respond to different drugs, we can make insightful predictions as to how that drug will behave in a patient,” said Bakal.

Using AI to streamline drug discovery

The research team is now focused on creating artificial intelligence (AI)-based technologies to aid in the selection of drugs to target the genes involved in cancer cell shapeshifting. Using AI to make predictions on drug success based on the 3D images of the cells could cut drug development times in half.

“We're trying to look at millions of cells in 3D across different conditions. This means there is a vast amount of complicated data that a human would find difficult to look at in a reasonable time frame. The AI techniques that we're developing will allow us to quantify and identify shapes in these very complex populations,” concluded Bakal.

Prof. Chris Bakal was speaking to Blake Forman, Senior Science Writer & Editor for Technology Networks.


About the interviewee:

Chris Bakal is a professor of cancer morphodynamics at The Institute of Cancer Research. He received his undergraduate degree in Biochemistry at the University of British Columbia and his PhD in Medical Biophysics at the University of Toronto and the Ontario Cancer Institute. His current research focuses on understanding how cells change shape, become cancerous and form metastases.

Reference: Dent L, Curry N, Sparks H, et al. Environmentally dependant and independent control of 3D cell shape. Cell Rep. 2024. doi: 10.1016/j.celrep.2024.114016