In response to nutrient changes in the environment, pancreatic cancer cells can adjust the rate of mRNA translation to selectively regulate the rate of protein production. However, the specific codons—the trinucleotide sequences that correspond to specific amino acids—and regulatory mechanisms used are not known. Dr. Banh’s research aims to decipher the laws governing how codons regulate mRNA translation in response to the nutrient environment in pancreatic cancers. As cancer cells have many codon-altering mutations and are constantly adapting to changes in the nutrient environment, these studies will offer insight into tumor evolution and may uncover novel therapeutic strategies for pancreatic and other cancer patients.

Pancreatic cancer develops in the midst of intense scarring and fibrous connective tissue (fibrosis). The architects of this scarring are cells called fibroblasts, known to fuel cancer growth and promote treatment resistance. Dr. Delitto's research is focused on the interface between cancer-induced fibrosis and the immune system. He has shown that fibroblasts play a significant role in shielding cancer cells from immune cells. By altering how fibroblasts sense tissue damage, Dr. Delitto has uncovered a mechanism that reactivates the immune system to fight the tumor. He aims to further develop these findings into a novel immunotherapy regimen for pancreatic cancer.

Current pancreatic cancer chemotherapies are not effective, and targeted therapies are only applicable in about 5% of cases. Furthermore, pancreatic cancers cause immune cell stress, limiting the success of immunotherapies in this disease. Using animal models and tumor samples from pancreatic cancer patients, Dr. Escobar-Hoyos [William Raveis Charitable Fund Innovator] has discovered that changes in RNA splicing, a process that controls protein diversity in cells, are crucial for pancreatic cancer development, therapy resistance, and disruption of anti-tumor immunity. She plans to dissect the molecular role of RNA splicing in pancreatic cancer, which likely drives the disease's lethality. She seeks to develop a novel anti-RNA splicing therapy with dual action-a targeted therapy against tumor cells coupled with an immunotherapy to restore immune cell anti-tumor activity-to more effectively treat pancreatic cancer patients.

Pancreatic cancer remains unresponsive to current chemotherapy and immunotherapy treatments. However, with the recent development of mRNA vaccines and drugs that target cancer cell mutations, there is hope for a new generation of immune-based therapies. The ability of adaptive immune cells, called cytotoxic T cells, to kill cancer cells is central to anti-tumor immunity. Using mouse models of human pancreatic cancer, Dr. Fraschilla [Merck Fellow] plans to identify the flags presented by cancer cells that enable T cells to recognize them as foreign and kill them. One category of flags that label cancer cells as foreign may be proteins from bacteria that prefer to replicate within the tumor environment. This investigation of cancer cell targets will inform the development of future vaccines to treat cancer and prevent tumor regrowth or metastases. Dr. Fraschilla received her PhD from Harvard University, Cambridge and her BS from Emory University, Atlanta.

Dr. Hananya [Robert Black Fellow] is investigating a component of the DNA repair machinery termed protein ADP-ribosylation. Our cells are constantly exposed to chemicals and electromagnetic radiation harmful to DNA. Since the integrity of our genetic material is critical, cells have evolved a variety of mechanisms to repair lesions in the DNA. But defects in these DNA repair pathways caused by genetic mutations can lead to genomic instability, which drives cancer development. Dr. Hananya is utilizing chemical biology to study ADP-ribosylation and to delineate its role in DNA repair. The research will provide vital information regarding cancer genesis and progression and will contribute to the development of new therapies.

Patients with the same cancer diagnosis may experience very distinct disease progressions and treatment responses. These differences between patients have been associated with their degree of intra-tumor heterogeneity-the genetic, epigenetic, spatial, and environmental differences between the tumor cells. Characterizing the genetic and epigenetic states of different tumor cells is key to understanding how intra-tumor heterogeneity influences tumor progression, expansion, metastasis, and treatment response. Recent advances in single-cell RNA sequencing and spatial transcriptomics (which shows the spatial distribution of RNA molecules within a tissue sample) provide new opportunities to study intra-tumor heterogeneity in higher resolution. Dr. Ma's research aims to characterize intra-tumor heterogeneity in terms of specific genetic and epigenetic measures, and eventually develop 3D tumor models that capture this heterogeneity across multiple cancer types. Dr. Ma received her BS from Zhejiang University and her PhD in computational biology from Carnegie Mellon University.

The proposed computational methods will be based on previous methods developed in the group. Dr. Ma will develop a better method for identifying tumor clones for spatially resolved transcriptomics (SRT) data using both copy number and allele information using HMM and HMRF. She will adapt optimal transport frameworks and include biological networks as prior knowledge for integrating epigenetic data with SRT and between SRT slices to construct 3D spatial tumor multi-omics models.

Obesity is a major risk factor for over a dozen cancer types, including pancreatic cancer, the third leading cause of cancer-related death in the United States. Despite the rising prevalence of obesity worldwide, surprisingly little is known about how it promotes cancer development. Using animal models that closely mimic human pancreatic cancer, Dr. Muzumdar showed that obesity could provoke abnormal signals sent by the hormone-producing cells of the pancreas to their neighboring tumor-forming cells. With this project, he aims to understand how these hormones are induced and act to drive cancer formation in obesity. Targeting pancreatic hormone signaling could provide a new approach for the prevention and treatment of pancreatic cancer and other obesity-associated cancers.

Oxygen is a double-edged sword in pancreatic cancer biology. Pancreatic cancers require oxygen, but they are amongst the most hypoxic of cancers, with oxygen concentrations as low as 200-fold below atmospheric oxygen concentrations. Pancreatic cancers use oxygen to make molecules critical for their survival and proliferation, but they are also vulnerable to oxidative stress, which is essential for the effectiveness of cancer treatments such as radiation. Dr. Pacold has developed techniques to determine which oxygen-dependent reactions are prioritized by pancreatic cancers and enhanced by radiation treatment, with the goal of identifying new targets that can be used for pancreatic and other cancers that are treated with radiation.

One in 64 people in the U.S. develops pancreatic cancer in their lifetime and only 9% will survive 5 years. This rate has barely changed in the last 40 years; better innovative treatments are urgently needed. Among the most promising immunotherapies is adoptive T cell therapy (ACT), which involves infusion of the patients' own immune T cells that have been engineered outside of their body to make them selectively kill cancer cells. ACT has been effective against certain blood cancers but has had limited success against solid tumors, including pancreatic cancers. Dr. Su will quantitatively assess the mechanisms that contribute to the decreased effectiveness of ACT against pancreatic cancer. He will use specimens obtained from mouse models and pancreatic cancer patients receiving ACT to develop computational frameworks that can be applied to single-cell sequencing data and other large datasets. His findings should inform the design of next-generation ACT against pancreatic cancer and potentially other solid tumors. Dr. Su received his BS from Tianjin University and his PhD in engineering/systems biology from the California Institute of Technology.

Dr. Su will develop and apply thermodynamic-inspired information-theoretical approaches to deconvolute the high-dimensional single-cell multi-modal data to resolve master-regulators contributing to adoptive cell therapy (ACT) ineffectiveness in the context of pancreatic cancer. In addition, he will utilize Bayesian statistical methods on the spatial multiomic data to reconstruct the cellular- and molecular factors that compromise the efficacy of ACT for pancreatic cancer in mice and humans.

Dr. Unlu studies how cancer cells adapt to nutrient limitations in their environment. High metabolic demands of proliferating cancer cells create metabolic bottlenecks for in vivo growth within solid tumors. Dietary and pharmacological interventions could provide unique opportunities to target such metabolic liabilities. However, studying tumor metabolism in vivo adds many layers of biological complexity, meaning these potential targets are currently poorly characterized. Dr. Unlu plans to combine metabolomics approaches and functional CRISPR screens to systematically identify metabolites limiting for in vivo tumor growth and metastasis.