Abstract I16: KRAS and environmental signals regulate MYC to drive lineage plasticity, pancreas cancer progression, and therapeutic resistance

Cellular plasticity in cancer is emerging as a biomarker of aggressive behavior and an important therapeutic resistance mechanism. The ability of cancer cells to switch lineage and differentiation states provides survival advantages in adverse tumor microenvironments and under therapeutic stress. Pancreatic ductal adenocarcinoma (PDAc) tumors display a dense immunosuppressive microenvironment and a high degree of cellular heterogeneity contributing to poor outcomes. Normally, pancreatic cellular plasticity allows for acinar-to-ductal metaplasia (ADM) in response to inflammation or injury as a reversible process and important mechanism for regeneration of functional tissue. However, mutant KRAS, which is a hallmark of over 90% of PDAc, drives ADM that progresses to ductal precursor lesions (PanINs) and PDAc. We have demonstrated that PDAc can further develop ductal to neuroendocrine lineage plasticity, and that this confers therapeutic resistance and is a biomarker of poor outcomes in patients. This discovery is consistent with other reports in prostate, lung, and breast cancer where neuroendocrine differentiation confers an aggressive, therapeutically resistant state. Mechanistically, we have demonstrated a role for the MYC oncoprotein in PDAc ductal - NE lineage plasticity. MYC is functionally activated by post-translational modifications to a conserved motif, Serine 62-Proline 63, in the MYC N-terminal transactivation domain. In PDAc, KRAS mutations and environmental signaling stimulate MYC Serine 62 phosphorylation and PIN1-mediated Proline 63 isomerization, which promote MYC DNA binding and regulation of pro-oncogenic target genes. We have also observed that cancer-associated fibroblasts (CAFs) can promote PDAc lineage plasticity and that the proline isomerase PIN1 involved in post-translational activation of MYC is also critical for fibroblast activation. Thus, PIN1 has a tumor cell intrinsic and stromal cell function, where loss of PIN1 in pancreatic stellate cells suppresses their activation to CAFs and their support of tumor growth. To understand crosstalk between the tumor microenvironment and cancer cell plasticity, and to develop effective therapeutic strategies that overcome this survival mechanism, we are using 3-D bioprinting to model tumor-stromal interactions and pursuing novel drugs that target post-translational regulation of MYC.