Author: admin

Researchers at UTHealth Houston have developed a patient-derived “tumor-on-a-chip” model designed to more precisely study pancreatic ductal adenocarcinoma (PDAC). The study, published in Advanced Science, details how the investigators designed the chip to integrate three-dimensional tumor organoids with components of the tumor microenvironment inside a microfluidic system to recreate interactions between cancer cells, stromal tissue, blood vessels, and immune cells.

“Our goal was to build a model that looks and behaves much more like a real pancreatic tumor than traditional lab models,” said Faraz Bishehsari, MD, PhD, professor and director of the Gastroenterology Research Center at McGovern Medical School at UTHealth Houston. “By recreating the tumor’s environment, we can better understand the disease and test treatments in a patient-specific way.”

Pancreatic cancer is difficult to treat because tumors exist within a dense and complex microenvironment that influences both tumor growth and drug response. Current in vitro methods to study the disease, such as two-dimensional cell cultures, as well as pancreatic cancer organoids, often fail to replicate these dynamics.

“Ex vivo models that replicate the tumor and its microenvironment can advance precision medicine in PDAC,” the researchers wrote, but noted that organoids alone “fall short in replicating the tumor microenvironment (TME), which includes various stromal and immune cells influencing tumor growth and chemoresistance.”

To address this, the UTHealth team combined patient-derived organoids with fibroblasts, endothelial cells, and immune cells in a microfluidic chip. The model was created using tumor and blood samples donated by consenting patients, which were used to grow organoids that retained the functional features of the original tumor. The organoids were then incorporated into a chip containing microfluidic channels that mimic blood flow and circulation to create a more dynamic interaction between cells types than current models.

The significance this new lab-on-a-chip lies in its ability to more closely replicate the tumor microenvironment as it would exist in humans more accurately than existing approaches. The design of the chip allows researchers to observe how tumors evolve over time, how stromal and immune components influence cancer behavior, and, perhaps most importantly, how potential drugs and therapies perform under conditions that more closely resemble human disease.

The researchers wrote that their chip “successfully recapitulated the in vivo cancer-stroma interaction of PDAC.” This included the formation of desmoplastic stroma, a dense, scar-like tissue known to limit drug effectiveness. This feature is difficult to reproduce in current PDAC models, but is known to be a major contributor to treatment resistance.

The chip allowed the team to test both chemotherapy and immunotherapies targeting PDAC. They showed that when stromal components were targeted in the model, the effectiveness of standard chemotherapy increased. For immune response, the team studied the effects of pembrolizumab to see how immune cells interacted with the tumor and showed that the drug enhanced T cell infiltration and tumor cell kill. Their observations that lower doses were less effective mirror patterns that have emerged in other clinical studies.

Based on these findings, the researchers noted that chip could serve as a tool for testing new drugs, studying mechanisms of resistance, and evaluating combination therapies tailored to individual patients. Because of its ability to closely recreate the way a tumor would react in vivo, the chip could serve as an important tool to identify the preclinical candidates most likely to effectively treat PDAC.

The implications for developing more precise PDAC therapies are significant. By incorporating organoids and tissues collected directly from individual patients, the chip could allow testing of individualized treatments to account for tumor heterogeneity. Further, it could help find ways to overcome drug resistance driven by stromal interactions and immune suppression.

Next steps for the research include improving the platform’s scalability and reproducibility to support broader use. Future work will also focus on incorporating additional immune components and refining the model to better reflect patient-specific tumor biology.

“This study shows that we can faithfully recreate key features of human pancreatic tumors, including interactions with stromal and immune cells,” Bishehsari said. “The next step is making these systems more practical so they can be widely used in research and drug development.”

The post Patient-Derived Lab-on-a-Chip Improves Precision Modeling of Pancreatic Cancer appeared first on Inside Precision Medicine.

Researchers have found a novel therapeutic target to enhance the effects of cancer immunotherapy. A study published today in Science Immunology reveals how a metabolite known as citraconate can reduce T cell exhaustion and enhance the ability of these immune cells to live longer, multiply, and effectively fight tumors. 

Despite the widespread success of checkpoint inhibitor immunotherapies, a substantial proportion of patients still do not respond to these treatments. One contributing factor is metabolic dysregulation within the tumor microenvironment (TME), which compromises the antitumor activity of tumor-infiltrating T cells and limits their proliferation, reducing the efficacy of immunotherapy.  

“Emerging evidence highlights the TME as a formidable metabolic barrier to immune cell function, attributable, in part, to the accumulation of immunosuppressive metabolites, which collectively promote T cell exhaustion and resistance to immunotherapy,” writes Lianjun Zhang, PhD, professor at the Suzhou Institute of Systems Medicine and senior author of the study. “Although tumor-derived metabolites are increasingly recognized as key modulators of T cell dysfunction and antitumor immunity, the critical metabolic circuits and specific metabolites that shape and sustain T cell phenotypes remain incompletely characterized.”

Citraconate is known to have antioxidative and antiviral properties, as well as being involved in T cell exhaustion. However, the exact signaling pathways it activates and immunological functions it plays in the context of cancer still remain poorly understood. 

Zhang’s team uncovered a previously unreported role for this metabolite in antitumor immunity, by reducing T cell exhaustion and preserving their ability to replicate. In tumor tissue samples from patients, the researchers found that citraconate was depleted within exhausted T cells. In cultured human cells and mouse models, supplementation with citraconate increased the activation of tumor-infiltrating T cells, promoted their division, and reduced exhaustion, boosting their antitumor activity. 

Further examination revealed that citraconate triggers these effects by increasing intracellular levels of cAMP, which in turn represses the ALOX5 enzyme involved in the oxidation of fatty acids such as arachidonic acid. This signaling cascade reduces the vulnerability of T cells to ferroptosis, a form of cell death driven by the accumulation of oxidized lipids on the cell membrane. 

Genetic and pharmacologic inhibition of ALOX5 enhanced antitumor immunity mediated by T cells, confirming these findings. In mouse models of cancer, supplementation with citraconate was shown to boost the effects of immune checkpoint therapy

Taken together, these findings unveil a critical metabolic checkpoint regulating the performance of tumor-infiltrating T cells, presenting a clinically actionable target to enhance the efficacy of immune checkpoint inhibitors. Going forward, the team plans to dive deeper into the signaling pathways that citraconate employs to modulate T cell activity, its role in metabolic regulation, and the potential contributions of epigenetics to the whole process. 

The post Citraconate Enhances Antitumor Activity and Reduces Exhaustion in T Cells appeared first on Inside Precision Medicine.