When asked to name common organs, people often think of the skin, brain, and liver. While these are all vital organs, they tend to overshadow another extremely important organ that is responsible for enabling digestion and regulating blood sugar: the pancreas. While the pancreas works normally most of the time, sometimes pancreatic cells cease function. Some pancreatic cells undergo tumorigenesis, the process during which normal, healthy cells turn into cancerous ones. What triggers this change? The answer lies in the dysfunction of specialized pancreatic cells, leading to the development of pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer-related deaths in the United States, originates from digestive enzyme cells that line the pancreatic duct. These specialized cells within the pancreas are responsible for breaking down carbohydrates, fats, and proteins, while also facilitating nutrient absorption. When these cells develop into PDAC, they become resistant to enzyme action, thereby creating greater regenerative properties for the cancer cells. With this enhanced regeneration, these cancerous digestive enzyme cells are able to withstand damage and continue to grow rapidly. The disease goes undetected because patients usually suffer from generic symptoms that are common in other conditions, leading to 80% of diagnoses being made when the disease is already advanced. As a result, the five-year survival rate is one of the lowest of all cancers, at 13%.
Dr. Michael Karin researches pancreatic cancer at UC San Diego. After unfortunately losing a friend to the disease, he believes greater education and training is required for physicians to improve patient care and survival outcomes. He describes how a multitude of deaths could be prevented if healthcare providers promoted more frequent familial cancer screenings and were hypersensitive to the generic symptoms indicative of PDAC, such as weight loss, abdominal or back pain, and jaundice. These issues motivated the need for further research and treatment development, thereby inspiring Dr. Karin’s work to fully understand pancreatic cancer, from its causes and risks to its molecular mechanisms and pathways.
The Karin lab uses in vitro pancreatic cancer organoids to gain a greater understanding of the disease and to research the efficacy of current treatments in order to develop novel ones. In-vitro organoids are 3D organ models that mimic an organ’s composition and functionality and are utilized outside the body. Organoids derived from pancreatic tumors harness the stem potential of these tumors, which is the ability to develop into a diverse range of cell types. This remarkable potential enables differentiation, where cells specialize into distinct types, allowing researchers to replicate tumors on a smaller scale and experiment with them ex-vivo, outside the organism. This specialized 3D culture technique creates more accurate and personalized research, allowing us to better understand the disease and how to treat it.
Dr. Karin started by focusing on the relationship between inflammation and cancer, noticing that high levels of inflammation lead to increased mitotic cell division rate, or the speed at which cells divide, and subsequently tumorigenesis. This initial finding was met with skepticism, as most experts believed mutations, or changes in DNA, and oncogenes (cancer-causing genes) were the driving forces behind cancer. However, once experimental controls were established, the researchers were able to produce more reliable data than previously obtained, leading to the conclusion that inflammation was also a risk factor for tumor development.
As previously mentioned, when pancreatic cells have an increased mitotic rate, they undergo tumorigenesis. These cells differentiate into pancreatic cancer stem cells (PCSCs), which further aid tumorigenesis and the cancer’s resistance to chemotherapy, rendering most therapies against PDAC ineffective. This has led to the development and usage of novel therapies that directly target and inhibit the genes associated with pancreatic cancer and PCSCs’ mechanism of action. In recent studies regarding the genetic activity of pancreatic cancer, antibiotics have proved promising in stopping tumorigenesis and metastasis, due to gene inhibition (switching off genes that promote cell growth). Specifically, the antibiotic salinomycin has been shown to inhibit PDAC tumor growth in mouse models. Another antibiotic, azithromycin, inhibits tumor formation by binding to a subunit of the bacterial ribosome.
Current treatments include surgery resection, which removes diseased areas of the pancreas, radiation, a cocktail of chemotherapy drugs, immunotherapy, and ablation. According to Dr. Karin, the preferred line of treatment is pancreatic resection, currently the least invasive treatment available. Using this treatment, the patient can live without a completely intact pancreas by taking enzyme pills and insulin. However, in most cases, the disease is so aggressive and has progressed to a point where a resection is not completely effective and full eradication of pancreatic tumors is not possible.
A variety of drugs that specifically target PCSCs and decrease their viability have also been effective in treating pancreatic cancer. For example, aspirin has been found to lower the activity of ALDH1, an enzyme responsible for fundamental cellular activities within PCSCs. Aspirin inhibits ALDH1’s involvement with NF-κB signaling, a pathway responsible for expressing pro-inflammatory genes that contribute to cancer development. Additionally, disulfiram, the drug used to treat alcoholism, minimizes the expression of cellular signalling pathways, like the NF-κB pathway, which are crucial in the development of cancer. The initial results are promising since a variety of drugs are effective in stopping tumor growth by targeting specific molecular components of the tumor. If effective, these therapies could sustainably cure PDAC and make it one of the most curable cancers.
Along with inflammation, ongoing research has established a bidirectional relationship between pancreatic cancer and the development of diabetes. Across different studies, researchers have shown that some patients who develop pancreatic cancer have already had diabetes or were considered prediabetic, which raises the possibility of a potentially strong link between diabetes and cancer. The Maike Sander Lab studies diabetes and the molecular mechanisms that affect insulin-producing beta-cells (β-cells) in the pancreas. These insulin-producing β-cells play a key role in secreting insulin, a hormone responsible for lowering blood glucose levels. People with diabetes either fail to produce enough insulin or develop a resistance to insulin, disrupting the regulation of blood glucose levels. This interrupts a healthy homeostasis, an equilibrium required in all bodily systems for proper functioning.
The onset of diabetes has been linked to pancreatic cancer growth, as resistance to insulin drives the pancreas to produce more insulin in an attempt to help regulate blood sugar levels. However, insulin also promotes cell growth, which creates a counterproductive “one step forward, two steps back” relationship, where the excess insulin produced to compensate for the deficit fuels the growth of cancer. Winnie Gong and Erika Agena, a master’s researcher and undergraduate student at the Sander lab, study the underlying molecular mechanisms of pancreatic β-cells. They use a variety of stem-cell islets, or disease-modeling cells for research, within stem cell models to represent what exactly occurs in diabetic patients. They look for metabolic pathways which produce ATP, the primary energy source for living things. The lab uses a seven-stage process to help differentiate the rate at which ATP is being produced in β-cell islet models. By testing specific pathways’ ATP output, they are able to identify and select which pathways to stop and manage insulin production.
The Sander Lab at UC San Diego has identified the folate pathway as a pathway of interest. While it is a metabolic pathway that is not a significant producer of ATP, it is responsible for regulating essential cell functions and metabolism. If this folate pathway is unchecked, it can lead to cellular mayhem, specifically affecting islet β-cells in the pancreas. The Sander Lab found that inhibiting the folate pathway improved insulin production levels. Their research’s findings have been replicated in a clinical trial where a patient with Type 1 diabetes regained insulin secretion ability in their cells, allowing the regulation of blood glucose levels. This research could potentially be used in developing a treatment for Type 2 diabetes and contribute to the ongoing research about the relationship between diabetes and pancreatic cancer.
The research conducted at the Karin and Sander labs at UC San Diego draws an interesting connection between pancreatic cancer and diabetes—two vastly different yet seemingly interconnected diseases. The relationship between diabetes and pancreatic cancer is complex; while we have no definitive answers just yet, this critical journey into understanding the complexities of these diseases allows us to develop treatments and cures. The groundbreaking research being conducted today, exemplified by the extraordinary efforts at the Karin and Sander labs, will carve a healthier and more informed tomorrow. Thanks to this remarkable research, we move closer to a future where the issue of pancreatic cell dysfunction is no longer a threat—a testament to the invaluable work being done at the Karin and Sander labs.
