Basal Marker ΔNp63α Is Enriched in Pancreatic Cancer Metastases but Not in Primary Tumors Post-Chemotherapy

Abstract

Cancer cells within a single pancreatic ductal adenocarcinoma (PDAC) are most often heterogeneous in their expression of the basal or classical transcriptional program. Predominance of the basal subtype has been associated with poorer patient outcomes and increased resistance to chemotherapy. Based on this, we predicted that basal subtype would be enriched in tumors previously treated with chemotherapy, and in metastases derived from primary PDAC tumors with a mixed basal/classical population. To create matched classical and basal cell lines, we stably transduced two classical PDAC cell lines (AsPC1 and HPAFII) with the basal program transcriptional driver ∆Np63α or an mCherry control and assessed their growth, metastasis, and response to chemotherapy both in vitro and in vivo. Forced expression of ∆Np63α successfully converted both cell lines to basal transcriptomic subtype, yet the basal program failed to drive increased cell growth or chemoresistance in culture and did not affect tumor growth of AsPC1 in the murine pancreas. In mice orthotopically engrafted with ∆Np63α-expressing cells, no statistically significant increase in spontaneous pulmonary metastases was observed for AsPC1 or HPAFII, however, pulmonary metastases were enriched for ∆Np63 expression as compared to established primary tumors, including expression of endogenous ∆Np63 in the mCherry control. Increased resistance to irinotecan chemotherapy was observed in ∆Np63α + HPAFII, yet treatment selected for ∆Np63-negative cells in both HPAFII and ASPC1. In summary, our data show that PDAC metastases are enriched for basal subtype, but chemotherapy treatment does not preferentially select for basal-type cells.