Working group Singh

The 10-year survival rate of pancreatic cancer (PDAC) patients is around 1%. Mortality rates in other cancers have considerably declined during the last decade, while PDAC is anticipated to become the second leading cause of cancer-related death by 2030. In Germany, around 18,000-to-20,000 people are diagnosed with PDAC annually. However, during this time period, almost equal number of patients died due to the severe disease complexity. On the one hand, incidence and mortality of PDAC are significantly associated with aging, which is a major in many European countries where the populations are aging rapidly. The hallmarks of PDAC include early tumor invasion, followed by local or distant metastasis, in more than 80% cases at the time of diagnosis. Unfortunately, PDAC patients who undergo surgical resection (20% of cases), often exhibit local or distant tumor recurrence because of the resilient micro-invasive tumor cells. Presently, surgical resection followed by an extensive chemotherapy remains the treatment option in all PDAC patients. Unfortunately, however, one third of PDAC patients’ exhibit tumor relapse within 3 years. While personalized therapeutic approaches are extremely limited, there is an urgent need for advancing molecular screening-based individualized stratification that may improve overall prognosis in PDAC patients.

Major biomedical challenges in pancreatic cancer prognosis and treatment

The complex molecular heterogeneity in tumor and stromal immune compartments resists conventional therapies and contributes to dismal prognosis and thus limits the patient stratification based therapy. Identification of transcriptomic-based subtypes has improved the early prognosis and therapeutic interventions in PDAC patients. For instance, transcriptomic profiling in PDAC specimens has revealed two distinct subtypes; the ‘classical’ and ‘basal-like’. The basal-like subtype is decisively linked to worse prognosis and therapy resistance, whereas the classical subtype is associated with a good prognosis. For details, please see our latest review article published in Trends in Cancer 2022 (PMID: 36117109).

Our Max-Eder research group is particularly interested in the precision medicine and translational cancer research. We strongly believe that a better molecular understanding of the complex tumor and stroma heterogeneity could significantly improve disease prognosis and therapy response in PDAC patients. Our most recent study demonstrates the molecular cross-regulatory networks between neoplastic subtypes and their associated stromal immune microenvironment in PDAC aggressiveness. We identified how these neoplastic subtypes shape the stromal immune microenvironment and thus modulate prognosis in preclinical models and patient-derived xenografts, including PDAC patient specimens. Specifically, our research group found that neoplastic-specific lineage-programs that determine intrusion of TNFα⁺-producing immune cells in the tumor microenvironment, and thus affect PDAC aggressiveness, resistant and overall prognosis. For further details, please see our recent publication in Nature Cancer 2021 (PMID: 35122059) and its preview in Cancer Discovery 2022 (PMID: 34862194).

On the other hand, metastatic pancreatic cancer (PDAC) has a poor clinical outcome with a 5-year survival rate below 3%. We have recently identified a new player, ‘axon guidance receptor ROBO3’ that promotes the metastatic and chemoresistant subtype in PDAC. Genetic or pharmacological inactivation of the ROBO3 signaling reduced ascites as well as liver metastases and restored chemosensitivity. In sum, this study uncovers a novel key mechanism in the regulation of metastatic subtype specification and supports current therapeutic concepts in PDAC aiming at subtype interference to overcome resistance. For further details, please see our recent publication in JCI Insight 2022 (PMID: 35993361).

What is still unknown?

• To what extent do tumor-extrinsic or -intrinsic events lead to pancreatic cancer heterogeneity during different clinical stages?
• How do chemo- and radiation therapy regulate pancreatic cancer plasticity and induce inflammatory tumor microenvironment?
• Can combining chemotherapy with subtype-specific epigenetic-transcriptional inhibitors be used to overcome unfavourable subtype switch?   
• How can we exploit knowledge on subtype switching to improve precision oncology in the clinics?