Pancreatic Cancer Heterogeneity
Christopher Heeschen, M.D. Ph.D.
Exploring stemness and therapeutic resistance via non-genetic evolution in cancer stem cells using single-cell omics.
Pancreatic cancer still has the worst outcome of any cancer around the world. At the same time, the incidence of pancreatic cancer keeps increasing, with currently ~500,000 new cases every year. This number is predicted to further increase in the coming years. Due to its extreme lethality with no effective treatments available at present, pancreatic cancer is currently the 3rd most frequent cause of cancer-related deaths, but may even become the 2nd most frequent cause by 2030. Pancreatic tumors are heterogeneous, not only because of diverse subclones that arise during tumor evolution, but also because they are driven by functional heterogeneity within each subclone. Such molecular and functional heterogeneity is a hallmark of multicellular life and controls pathogenesis in many diseases. Conventional bulk molecular analysis of cancer cells is masking smaller subclones and, even more importantly, key subsets of cells within these subclones that are characterized by enhanced stemness and functional plasticity. This has led to the development of therapies that mostly address dominating clones and cell populations. Recent advances in precision medicine and immunotherapy have entirely failed to improve the outcome of pancreatic cancer.
The molecular and functional heterogeneity of pancreatic cancer is, at least in part related to a distinct subset of cancer cells with enhanced stemness features. Convincing evidence from our lab demonstrates that these cells are uniquely capable of propagating the tumor, much like normal stem cells fuel proliferation and differentiation in normal tissue, therefore termed cancer stem cells (CSCs). Such CSCs, down to a single cell, are capable of initiating and reconstituting heterogeneous tumors, maintain their tumorigenic potential during serial transplantation, are essential for metastasis, and a main culprit for drug resistance. We have also shown that genetic targeting of stemness dramatically enhances the response to current standard medical care. Therefore, targeting stemness by disrupting the underlying transcriptional circuitry should prevent tumor relapse and improve long-term outcome.
Conclusions and perspectives:
Our research efforts center on large-scale and high-resolution interrogation of (metastatic) cancer stem cells in their natural microenvironment using functional genomics. We use valuable fresh patient material, single-cell omics technologies, and complementary approaches for functional taxonomy of cancer stem cells. This will define the landscape of stemness and therapeutic resistance via non-genetic evolution in cancer stem cells and provide the basis for developing novel, more effective treatment strategies.
The three overarching high-level objectives of our research program are:
- Identify and validate novel and common targets that are vital for cancer stem cell functions, specifically focusing on the Chinese patient population.
- Develop multimodal therapeutic strategies to jointly eliminate cancer stem cells, differentiated cancer cells and the protective stroma.
- Test these novel treatment strategies using precision medicine approaches.
The underlying hypothesis for our research program is that comprehensive functional interrogation of cancer stem cells results in the identification of novel targets with broad applicability. Inhibition of these newly defined pathways will reduce CSC content and thus prevent tumor relapse during/following treatment. Using cutting-edge technologies developed in our own lab, we are systematically identifying common regulators that control stemness, metabolism and immune privilege in pancreatic cancer. Our studies are directly relevant to improving therapy in pancreatic cancer. The ultimate goal of our research relies on the development of new multimodal treatment regimens that generate rapid and significant impact on pancreatic cancer progression (i.e. doubling or greater in the median survival for pancreatic cancer patients).