Cancer cell subpopulation and host crosstalk during metastasis of pancreatic ductal adenocarcinoma (PDAC)

• Applicant: Privatdozentin Dr. Yuan-Na Lin, Ph.D.
• Subject Area: General and Visceral Surgery
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429807806

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options and a dismal prognosis, largely due to its high metastatic risk and resistance to treatment. A major impediment to effective treatment of patients with PDAC is intratumor heterogeneity, which is shaped during cancer evolution by local and systemic interaction with the host. The two major characteristics of the PDAC microenvironment are dense desmoplasia and extensive immunosuppression. The tumor-associated stroma evolves to facilitate cell proliferation, the evasion of immune surveillance and metastasis. Our and other recent studies revealed distinct sensitivity of clonal subpopulations from a primary tumor to immunotherapy, which was affected by cell-intrinsic factors, as well as tumor-stromal and –immune cell interactions. Moreover, PDAC clonal cell-intrinsic effects modulate the immune microenvironment, which correlates with metastatic efficiency.In this project, we aim to understand how the crosstalk between PDAC clonal subpopulations, and with the host contributes to the metastatic capacity of metastasis-initiating cells (MICs). By using defined mixtures of clonal cell lines, isolated from a KPC (KrasG12D/+; Trp53R172H/+; P48-Cre) mouse pancreatic tumor, we aim to identify soluble factors, e.g. cytokines, that support metastatic behavior of MICs. The effects will be examined in vitro and in vivo. By drug treatment or genetic interventions, we will further decipher the effects of this clonal cell-intrinsic regulation on the immune microenvironment of primary tumor and metastases in immunocompetent mice. This approach aims to reveal unique drivers within tumor subpopulations that influence metastatic capacity and resistance to immunotherapy. Our goal is to transfer this knowledge to the clinic, in order to improve sensitivity to immunotherapy in patients with PDAC for efficiently targeting the metastatic state.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Anton Wellstein