We have found that reprogramming of cancer-associated fibroblasts by Prrx1 deletion restrains pancreatic cancer progression and metastasis. These data highlight the possibilities of new treatment strategies through the conversion of tumor-promoting CAFs into tumor-restraining CAFs. Read more in our new publication in Gastroenterology „Mesenchymal plasticity regulated by Prrx1 drives aggressive pancreatic cancer biology“.
Dynamic cell fate decisions, including cellular plasticity, are critical for the development of resistance to chemotherapy, contributes to cancer heterogeneity and drives the metastatic process in pancreatic cancer. We have previously identified the paired-related homeobox 1 (Prrx1) transcriptional factor as driver of cellular plasticity in pancreatic cancer. However, cellular plasticity is not restricted to tumor cells but is also present in cancer-associated fibroblasts (CAFs). The role of Prrx1 in CAFs has not been addressed so far.
Importantly, we found that high stromal expression levels of Prrx1 are associated with the squamous subtype, whereas low stromal Prrx1 expression is found in classical PDAC, thereby indicating a potential functional role of Prrx1 in CAFs. Consequently, we developed a conditional knockout allele of Prrx1 in order to specifically ablate Prrx1 in fibroblasts, both in vitro and in vivo. Mechanistically, we describe that loss of Prrx1 mediates CAF activation, leads to increased amounts of ECM, improved tumor differentiation, fewer circulating tumor cells and reduced metastasis. At the same time, Prrx1 in CAFs promotes EMT and chemotherapeutic resistance in tumor cells through paracrine HGF signaling.
Photo: PD Dr. med. Maximilian Reichert (PI), Dr. rer. nat. Karin Feldmann (Postdoc)