Starving Tumors: How It Improves Cancer Treatment
Blocking Cellular ‘Scavenging’ boosts Pancreatic Cancer Treatment Response
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Pancreatic ductal adenocarcinoma (PDAC),one of the deadliest forms of cancer,is notoriously difficult to treat. Now, a groundbreaking study from Sanford Burnham Prebys reveals a potential strategy to overcome this challenge: blocking a cellular process called macropinocytosis in cancer-associated fibroblasts (CAFs). This approach not only weakens the tumor’s support system but also enhances the effectiveness of immunotherapy and chemotherapy, offering new hope for patients.
Pancreatic cancer cells are remarkably adept at scavenging nutrients from their surroundings, a process crucial for their survival and growth. Macropinocytosis, a form of cellular “drinking” where cells engulf large volumes of extracellular fluid, allows these tumors to grab onto essential resources, especially glutamine – an amino acid vital for protein building.
“PDAC relies upon glutamine much more than other cancers,” explains Yijuan Zhang,PhD,staff scientist at Sanford Burnham Prebys and lead author of the study. “CAFs in the pancreatic cancer tumor microenvironment are routinely starved of glutamine, and macropinocytosis helps them compensate, providing growth signals, and also helping in other ways.”
However, this scavenging isn’t limited to cancer cells. CAFs, cells that surround the tumor and contribute to its microenvironment, also utilize macropinocytosis. Researchers discovered that inhibiting this process in CAFs has a surprising and beneficial effect.
reprogramming the Tumor Microenvironment
The study revealed that blocking macropinocytosis in CAFs doesn’t simply starve them; it fundamentally alters their behavior. When deprived of this scavenging mechanism, CAFs shift from a subtype that promotes tumor stiffness and density (myofibroblasts) to one that triggers inflammation.
“Moast pancreatic CAFs are myofibroblasts that promote stiffness and density in the tumor microenvironment and make it more difficult for immune cells and drugs to reach the tumor,” says Cosimo Commisso, PhD, senior author and interim director and deputy director of the institute’s cancer centre. “Our experiments led to a subtype reprogramming with fewer myofibroblasts and more inflammatory CAFs, and we wondered how this change would affect the overall tumor microenvironment.”
The resulting changes were significant. The team observed:
Reduced Tumor stiffness: Less collagen deposition meant a less fibrotic, more pliable tumor surroundings.
Enhanced Immune Cell Infiltration: More CD4+ and CD8+ T cells, crucial immune fighters, were able to penetrate the tumor.
Improved Vascularization: blood vessels widened,potentially improving drug delivery.
These modifications create a more hospitable environment for cancer treatments to work effectively.
Synergistic Effects with Immunotherapy and chemotherapy
To test the clinical potential of this discovery, the researchers combined a macropinocytosis inhibitor (EIPA) with existing therapies. The results were compelling.
when combined with immunotherapy,specifically an anti-PD-1 antibody,EIPA considerably suppressed tumor metastasis and prolonged survival in mouse models. PD-1 is a protein on T cells that can dampen the immune response, and blocking it allows the immune system to attack cancer cells more effectively.
Similarly, pretreating mice with EIPA before administering the chemotherapy drug gemcitabine led to synergistic tumor growth suppression and reduced the spread of micrometastases to the lungs.
“Our findings were similar when using EIPA as a pre-treatment before using the chemotherapy gemcitabine,” Zhang confirms. “In addition to synergistically suppressing tumor growth in mice with PDAC, it also reduced the spread of micrometastases in the lungs.”
A Promising New Avenue for Cancer Treatment
The research team is now focused on further exploring ways to disrupt tumor energy scavenging and reshape the tumor microenvironment to maximize treatment efficacy.
“We believe this is a very promising strategy to pursue for developing combination therapies for cancer patients,” Commisso states. “Especially for pancreatic cancer that is the third leading causes of cancer deaths despite accounting for only three percent of cases.”
This research offers a compelling new target for pancreatic cancer treatment, potentially transforming the landscape for patients facing this devastating disease. By targeting the tumor’s support system and boosting the immune response,this approach coudl significantly improve outcomes and offer a much-needed lifeline for those battling PDAC and other cancers reliant on macropinocytosis.
additional authors include: Li Ling,Rabi Murad,Swetha Maganti,Ambroise Manceau,Hannah A.Hetrick, Madelaine Neff, Cheska Marie Galapate, shea F. Grenier, Florent Carrette, Karen duong-Polk, Anindya Bagchi