A cellular recycling process called autophagy helps determine whether pancreatic cancer cells grow quickly or hunker into survival mode to resist treatment, a study showed.
The researchers found that autophagy in pancreatic cancer cells is regulated by connections between the cancer cell and surrounding structural proteins. The findings shed new light on how pancreatic cancers resist cancer treatments and may pave the way for new therapeutic approaches, researchers said.
The study, “Extracellular matrix sensing regulates intratumoral heterogeneity of autophagic flux,” was published in Cell. The National Institutes of Health and the Lustgarten Foundation provided funding.
Autophagy, derived from Greek words meaning self-eating, is a process in which cells break down parts of themselves to generate nutrients. This self-cannibalizing process can help cells survive when resources are scarce, and there’s growing evidence that cancer cells can activate autophagy to resist treatments. The molecular mechanisms governing autophagy in cancer cells, however, are poorly understood.
Using 3D cell models designed to mimic the tissue architecture of tumor cells in the human body, researchers analyzed autophagy activity on a cell-by-cell basis. They found that the cancer cells could be broadly divided into two groups: some with low autophagy and some with high autophagy.
Cells with low autophagy grow faster
Data indicated that cancer cells with low autophagy levels tended to grow faster, making more new cancer cells. However, these fast-growing cells were also relatively more sensitive to chemotherapies that are used for pancreatic cancer. In contrast, cancer cells with high autophagy levels grew much more slowly, but they were better at resisting chemotherapy.
In a further battery of tests, the researchers sought to better understand the molecular mechanisms regulating these differences in autophagy levels. They found that autophagy is regulated by interactions with the extracellular matrix (ECM), the network of structural proteins that surround cells and help hold them in place within the body’s tissues.
“Our findings show that the sensing of the ECM by pancreatic cancer cells enables them to switch between states of active growth and autophagic survival,” Mohamad Assi, PhD, a postdoctoral fellow at New York University Langone Health, said in a press release from the medical center.
The scientists found that pancreatic cancer cells express a surface protein, integrin-alpha3 (ITGA3), that binds to certain ECM proteins. When ITG3A sticks to the ECM, it activates a signaling pathway called the Hippo-YAP1 axis inside the cell. This, in turn, shuts down autophagy. But when ITG3A isn’t attached to the ECM, the Hippo-YAP1 axis is turned off, leading to increased autophagy levels.
The researchers validated their findings in clinical specimens, showing that pancreatic cancer cells with high Hippo-YAP1 axis activity also had low levels of autophagy markers. Collectively, these data suggest that “targeting the ITGA3-Hippo-YAP1 axis could be exploited to hinder the intrinsic ability of [pancreatic cancer] cells to actively grow, survive under stress, and tolerate [cell-killing] drugs,” the researchers concluded.
The only FDA-approved drug that targets autophagy is hydroxychloroquine, a medication used to treat malaria. Studies have indicated that hydroxychloroquine isn’t especially effective on its own as an anticancer agent. These new data may suggest why, the researchers said — the findings suggest that tumor cells can switch to low autophagy by attaching to the ECM through ITG3A, which would theoretically make them more resistant to hydroxychloroquine.
The researchers found that blocking ITG3A forced the cancer cells into a state of high autophagy flux, and hydroxychloroquine was much more effective at killing pancreatic cancer cells in their model.
“We demonstrated that the ITGA3-Hippo-YAP1 axis could be leveraged to modulate autophagy levels … and create a targetable vulnerability,” allowing cancer cells to be killed by treatment, the researchers said. The findings, they said, lay the groundwork for further efforts to target this pathway as an anticancer treatment strategy.
The post Pancreatic cancer growth tied to cells’ self-eating process appeared first on Rare Cancer News.