Mechanism: Understanding the role of cell plasticity in cancer
Adaptive cell fate decisions in response to changing microenvironmental conditions, including therapy-imposed selective pressure, are fundamental to tumor evolution. Cellular plasticity enables tumor initiation, detachment from the primary lesion, dissemination, and metastatic outgrowth. At the same time, plasticity fuels intratumoral heterogeneity, promotes immune evasion, and underlies resistance to therapy, making it a central mechanistic principle of cancer progression.
Transcription factor isoforms execute distinct functions in PDAC progression and metastasis
We identified the transcription factor Paired-related homeobox 1 (Prrx1) as a central regulator of cellular plasticity in pancreatic ductal adenocarcinoma (PDAC) (Reichert et al., Genes & Development, 2013). Using complementary in vitro and in vivo models, we uncovered opposing roles of Prrx1 isoforms in metastasis: Prrx1b promotes invasion, dedifferentiation, and epithelial-to-mesenchymal transition, whereas Prrx1a drives metastatic outgrowth, tumor differentiation, and mesenchymal-to-epithelial transition (Takano, Reichert et al., Genes & Development, 2016). Isoform switching between Prrx1b and Prrx1a governs EMT plasticity in both mouse models and human PDAC. Mechanistically, we identified hepatocyte growth factor (HGF) as a direct transcriptional target of Prrx1b, and combined targeting of HGF with gemcitabine suppressed primary tumor growth and eliminated metastases in preclinical PDAC models. These findings directly informed a phase 1b clinical trial (NCT03316599).
Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer
Epithelial plasticity critically depends on the ability of cancer cells to establish and release cell–cell contacts, a process stabilized by membranous E-cadherin through its interaction with p120-catenin (p120ctn). Using complementary genetically engineered mouse models, we demonstrated that metastatic organotropism in pancreatic ductal adenocarcinoma (PDAC) is governed by p120ctn-mediated epithelial identity (Reichert et al., Developmental Cell, 2018). Mono-allelic loss of p120ctn accelerates KrasG12D-driven PDAC formation and promotes liver metastasis while preserving E-cadherin–dependent adhesion, whereas bi-allelic loss shifts metastatic tropism toward the lung. Rescue of p120ctn restores liver metastasis, and in p120ctn-independent models, mosaic E-cadherin loss reveals selective pressure for E-cadherin–positive liver and E-cadherin–negative lung metastases. Together, these findings establish epithelial plasticity as a key determinant of metastatic organotropism and provide a mechanistic explanation for the more favorable prognosis of PDAC patients with isolated lung metastases.
Cancer-associated fibroblast plasticity drives aggressive pancreatic cancer biology
Dynamic cell fate decisions in pancreatic ductal adenocarcinoma (PDAC) extend beyond tumor cells to the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), whose differentiation states determine tumor-promoting or tumor-restraining functions. We identified PRRX1 expression in the stromal compartment of murine and human PDAC, where high stromal PRRX1 levels associate with the aggressive squamous subtype, while low expression characterizes classical PDAC, suggesting a functional role for PRRX1 in CAFs (Feldmann et al., Gastroenterology, 2021). Using a fibroblast-specific conditional Prrx1 knockout, we demonstrated that loss of Prrx1 induces CAF activation, increases extracellular matrix deposition, improves tumor differentiation, reduces circulating tumor cells, and suppresses metastasis. Mechanistically, PRRX1-expressing CAFs promote epithelial-to-mesenchymal transition and chemoresistance in tumor cells via paracrine HGF signaling. Notably, Prrx1-deficient CAFs remodel the tumor microenvironment toward an immune-infiltrated state, revealing fibroblast plasticity as a tractable therapeutic vulnerability to convert tumor-promoting into tumor-restraining stroma.