Designing Novel Strategies to Target Tumor-Promoting Functions of Pancreatic Cancer Fibroblast Subtypes
Abstract
Pancreatic cancer has no cure, and 9 in 10 patients die within 5 years of diagnosis. This dismal prognosis is partly due to the lack of effective therapies. Efforts to develop novel treatments have largely focused on blocking the cancer cells despite non-cancerous elements comprise up to 90% of the tumor and contribute to disease progression. Among these non-cancerous cells, so-called cancer-associated fibroblasts (CAFs) are the most abundant and play critical roles in promoting tumor growth and therapy resistance. Therefore, our proposal addresses two FY21 PCARP Focus Areas: (1) Understanding the relationship between oncogenic signaling and the tumor microenvironment, and (2) Developing new drugs targeted toward cancer sensitivity and resistance mechanisms. Previous attempts to therapeutically target CAFs in pancreatic cancer have led to conflicting results, indicating that CAFs may have both tumor-promoting and tumor-restraining functions. Indeed, we discovered that pancreatic CAF populations exist in two main states with distinct features, suggesting that they can impact cancer progression in different ways. However, their specific functions remain unclear. Understanding the roles of these CAF populations is central to developing effective CAF-directed therapies for pancreatic cancer. It has been extremely difficult to determine the roles of distinct pancreatic cancer CAF populations because these CAFs are dynamic and can interconvert. Additionally, there are limited markers and tools to selectively target these CAF populations and thus reveal their functions. We have overcome the CAF plasticity problem by engineering cells that are locked in a specific CAF state and cannot interconvert. Using these novel cell lines, we will perform an in-depth interrogation of the two predominant CAF populations in pancreatic cancer. First, we will comprehensively profile the cell surface of these CAFs to identify new unique markers and antibody-based tools to selectively detect and target each population. Second, we will define how these CAF populations impact tumor cells directly or indirectly through effects on immune cells, and in the context of therapies. Third, we will evaluate the potential of targeting specific tumor-promoting functions of these CAFs using genetic and pharmacological strategies. Our proposed studies will identify novel markers, targets, and tools to profile, detect, and selectively block specific tumor-promoting roles of pancreatic cancer CAF populations. These resources will be made widely available to other pancreatic cancer researchers and clinicians for further investigation of pancreatic cancer biology. We anticipate that our findings will guide the future application of new CAF markers that will be predictive of therapy response, and the development of novel rationally designed combination therapies, which will translate into future benefit for pancreatic cancer patients. Collectively, our work will greatly expand our knowledge of CAF biology and functions and will spark the development of novel therapeutic strategies that will improve, in the long term, the survival of pancreatic cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210829
Entities
People
- Tobiloba E Oni
Organizations
- United States Army
- Whitehead Institute