Optical imaging highlights metabolic interaction

Pancreatic cancer is a rare but elusive and deadly cancer with a five-year survival rate of about 10%. If the cancer has metastasized, this rate drops to 3%. And treatment options are extremely limited.

“It’s one of the scariest cancers because once you find out someone has pancreatic cancer, it’s often too late because there are no symptoms,” says Rupsa Datta, scientific assistant at the Skala Laboratory. “The survival rate is so low because at that point you really can’t do anything.”

The Skala lab uses advanced optical imaging to study the metabolic activity that leads to tumor growth, in the hope that a better understanding of the tumor microenvironment may lead to new therapies and treatments.

In a study published today in the journal Scientists progress, Datta and colleagues describe how cancer cells can hijack the metabolic activity of certain non-cancerous cells in the pancreas to fuel tumor growth.

When cancer cells begin to proliferate, the extracellular matrix (ECM) becomes part of the tumor microenvironment, a network of molecules that help structure the cells that make up an organ like the pancreas.

Non-cancerous cells also exist in the ECM, such as immune cells, fibroblasts, and organ-specific support cells like pancreatic stellate cells (PSCs).

It’s the interactions between cancer cells and these CSPs that are critical to cancer proliferation and survival, Datta says.

“Cancer cells can recruit these non-cancerous cells to work for them,” she says. “It’s as if they were under the spell of the cancerous cell. They will supply them with nutrients and other things so that the cancer cell can survive.

The researchers combined pancreatic cancer cells and PSCs into an organoid model, a 3D cell culture environment in a gel-like matrix structure that more closely mimics the biology of a living organ or tumor.

Optical metabolic imaging allows researchers to visualize and measure metabolic interactions between cells in real time. The technique is non-invasive and label-free, which means it uses the cells’ innate autofluorescence as the readout instead of adding other reagents that would damage the cells.

Changes in metabolism are measured by the reduction-oxidation state of cells, or redox state, which fluctuates as electrons are transferred between molecules in a cell to help them grow and divide.

“We found that when these non-cancerous cells are present, the redox state of the cancer cells becomes more oxidized and progresses towards proliferation,” says Datta. “When the CSPs hit the cancer cells, they became smaller and smaller.”

This transfer between cells suggests that cancer cells could overcome their redox limitation of cell proliferation by directly interacting with PSCs and exploiting the metabolic process to support cancer growth.

It is still unclear exactly how the physical interaction between these cells results in redox state changes. But Datta hopes that a better understanding of these interactions will ultimately lead to targeted therapies that prevent cancer cells from proliferating and tumors from developing.

For this study, the Skala Lab worked closely with a cancer biologist Matt Vander Heiden and his laboratory Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), with funding from the nonprofit organization Stand up to cancer (SU2C).

“Most of our collaborators are in Wisconsin, but this was a remote collaboration, so with the grant, I could go to their lab and they could come here too,” Datta says. “It was a very interesting project because we have expertise in different fields. And we both have to answer these questions.

Datta says that while the Skala Lab was developing the advanced imaging techniques to obtain these metabolic measurements, the Vander Heiden Lab was integral in setting up the organoid model and putting the data into biological perspective and its relevance in the field of cancer.

“I hope this article will show the power of our technique. However, if more cancer labs adopted it, they would still need to collaborate with labs like ours with imaging expertise,” she adds. “But we like to collaborate!”

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