Probes for KRAS

Transforming Growth Factor Beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway, through its interaction with the serine/threonine kinase type I and II heterodimeric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression and its effects on acinar cells have so far remained elusive.

We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA) in the pancreatic acinar compartment.

We observed that TβRICA expression induced Acinar-to-Ductal Metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous PanINs (Pancreatic Intraepithelial Neoplasia). This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, while at the molecular level, we evidenced a modulation in the expression of transcription factors, such as Hnf1β, Sox9 and Hes1.

We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation, through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients.