Pancreatic cancers are aggressive and deadly, with high rates of metastasis and poor prognosis. The tumour environment is also hypoxic: the cells rapidly divide and thrive in very low oxygen conditions.
Now, IIT-Bombay researchers have shown that the hypoxia ends up enhancing the cells’ metastatic behavior. By affecting the cells’ plasma membrane lipids, hypoxic conditions can help the cells migrate more.
“The membrane is not just something that is covering the cell and keeping everything that should be inside, inside, and everything that should be outside, outside,” said BITS Pilani biophysicist Sudipta Maiti, who wasn’t involved in the work. “It is also the cell’s window to the outside world.”
Stiff yet malleable
In two studies published in 2023 and 2025, IIT-Bombay chemist Shobhna Kapoor and her colleagues showed that hypoxia can modify the kinds of lipids present in the cancer cells’ plasma membrane, thus affecting how easily the cells are able to fluidise and move around. In the 2023 Biochimica et Biophysica Acta paper, they reported that hypoxia causes the cells of the PANC-1 pancreatic cancer cell line to migrate more. This happened because hypoxia was able to modulate the lipid ratios in the cells: lipids that promote membrane stiffening were pushed towards the cytoplasm and inner organelles. They also observed that the cells had less cortical stiffness, meaning the layer of skeleton just below the membrane allowed for more fluidity.
In the Journal of Membrane Biology study published in August, the researchers studied a different cell line called CAPAN-2. In contrast, researchers found that this pancreatic cancer cell line had higher cortical stiffness in response to hypoxia. But it still maintained its malleable nature by adding more membrane components to its plasma membrane. Even the lipidome modifications were different in this case, with some lipids that promote membrane stiffening making their way to the plasma membrane. But the scientists believe that this is a local stiffening effect and doesn’t affect the overall membrane properties.
Even though hypoxia affected cell stiffness differently in the two pancreatic cancer cell lines they studied, the cells still modified their own membrane in a way that their migration increased when oxygen was low. Together, the studies could open new pathways that could both contribute to and prevent excessive cell migration in pancreatic cancer cells and modulating them could potentially help mitigate the tumour from metastasising.
In for a surprise
When Dr. Kapoor and her student initially realised that hypoxia caused the PANC-1 cells to migrate faster, they decided to check how the membrane’s biophysical properties — like how ordered, fluid or bendy the membrane was — were changing. But they were in for a surprise when they found that some broad properties of the membrane didn’t change dramatically.
“Then we decided let us then not look at ensemble properties of the membrane, maybe let us look at the composition of the membrane,” Dr. Kapoor said. “And then we realised that actually, the hypoxia is changing the lipidome of the cell.”
They found that even though the cell seemed to be increasing its amounts of membrane-stiffening lipids, like lipids with long fatty-acid chains or saturated bonds, the lipids in the plasma membrane didn’t change as much.
“There is a feedback loop that is going on which helps the membrane to maintain homeostasis so that the membrane properties remain the same,” said Dr. Kapoor. “The changes that the hypoxia brings about in the lipid levels, they get compensated in internal organelles like nucleus, mitochondria, and endoplasmic reticulum.”
They also found that the PANC-1 cells had less cortical stiffness because of low actin volume. With low stiffness and any membrane-stiffening lipids being trafficked inwards, the cell could maintain a malleable membrane that helped it migrate, the researchers speculated.
‘Like tadpoles’
The story is slightly different for CAPAN-2. Hypoxia still helped the cells migrate more, but their cortical stiffness was higher in hypoxic conditions. But other experiments revealed that the cell was trafficking more membrane material to the plasma membrane, to counteract this stiffness and likely maintain its migratory behaviour.
The researchers also found an increase in saturated lipids in the plasma membrane, suggesting that the cell may also be trying to locally enhance the membrane stiffness.
“There seems to be some diversity from one cell type to another,” said Mohammed Saleem, a biophysicist at the National Institute of Science Education and Research, Bhubaneshwar. “[Some] changes are sensed by the cells, and they try to re-equilibrate so as to counter the changes.”
Dr. Maiti said solid-state nuclear magnetic resonance (NMR) — a technique that uses magnetic fields to look at the atomic level structure and dynamics of solid molecules — could probe deeper into the plasma membrane and figure out how exactly hypoxia could be changing its properties.
“Lipid molecules are like tadpoles: it’s a little head and a little tail and the whole thing is probably two nanometers long. Solid-state NMR can look at this little tail and see how dynamic it is,” he explained.
“It [can be] fluctuating madly or pretty stable because the lipids are packed, [which] translates into mechanical property — how stiff something is, how loose something is. It’ll be nice to show quantitatively, using solid-state NMR, how hypoxia leads to change in this membrane order.”
Effects on other cancers
Both Dr. Kapoor and Dr. Saleem said that going forward one must also explore how hypoxia affects other cancers.
“Each of these cancerous cell types have their own niche and microenvironments,” Dr. Saleem said. “It would be interesting how hypoxia and the differences in those microenvironments could come into play to drive the migration.”
“A small biochemical reaction [causing hypoxia] can induce a larger physical manipulation of the cell membrane, [helping] the cells migrate faster,” Dr. Saleem added. “This could also open up venues for exploring membrane targeted anti-cancer therapeutics.”
Rohini Subrahmanyam is a freelance journalist in Bengaluru.
Published – November 25, 2025 11:30 am IST
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