Disruption of stromal hedgehog signaling initiates RNF5-mediated proteasomal degradation of PTEN and accelerates pancreatic tumor growth

Abstract

Disrupting paracrine Hedgehog signaling in pancreatic cancer stroma through genetic deletion of fibroblast Smoothened leads to proteasomal degradation of fibroblast PTEN and accelerates tumor growth.

PTEN Function at the Interface between Cancer and Tumor Microenvironment: Implications for Response to Immunotherapy

“…These observations correlate with aggressive tumor features and worse prognosis [ 93 ]. PTEN-loss in PDAC fibroblasts is usually associated with the ablation of the smoothened (Smo) gene, resulting in PTEN degradation by the E3 ubiquitin ligase RNF5: proteasome-dependent PTEN inactivation leads to increased proliferation and reduced overall survival (OS) [ 94 ].…”

The Role of Smoothened in Cancer

“…AZD8542, a novel HH antagonist, inhibited the progression of pancreatic cancer with an emphasis on the role of the stroma compartment [ 97 ]. The ablation of the SMO gene in stromal fibroblasts caused increased proliferation of pancreatic tumor cells and the activation of oncogenic protein kinase B (AK1) in fibroblasts [ 98 ]. A SMO inhibitor increased the intratumoral vasculature [ 99 ].…”

Application of 3-D Microfluidic Models for Studying Mass Transport Properties of the Tumor Interstitial Matrix

“…Furthermore, it was shown that K was rescued to control levels by targeting PDGFR-α with the tyrosine kinase inhibitor (TKI) crenolanib, and extracellular hyaluronic acid (HA) deposited by stromal fibroblasts with hyaluronidase (HAdase). Recently, it was shown that pharmacologic inhibition of smoothened (SMO) in human pancreatic cancer fibroblasts with the compound GDC-0449 (or vismodegib) destabilized phosphatase and tensin homolog (PTEN) (Pitarresi et al, 2018). Moreover, gene expression analysis revealed that treatment of these fibroblasts with GDC-0449 increased hyaluronan synthase 3 (HAS3) expression levels while microfluidic analysis demonstrated that GDC-0449 treatment reduced K , which was rescued to control levels with application of HAdase.…”

“…Therefore, successfully elucidating these roles by ECM components besides collagen and HA may lead to new therapies for targeting the matrix that can improve drug transport and patient outcomes. We note that the application of microfluidic models has so far focused on describing the transport properties of desmoplastic tumors such as breast and pancreatic carcinomas that are rich in collagen and HA (Gioiella et al, 2016; Hammer et al, 2017; Brancato et al, 2018; Pitarresi et al, 2018). However, with increasing information on the different ECM compositions across various tumor types (Naba et al, 2016), measurements of the interstitial ECM transport properties can also be applied to non-desmoplastic tumors such as brain cancer to provide novel insights.…”

“…Another prospective application for measuring D and K ′ within microfluidic devices can involve rapid screening to predict functional outcomes based on different genetic profiles of tumor or tumor-associated cells. For example, we previously demonstrated that hyperactivation of PDGFR-α in mammary fibroblasts and loss of PTEN in pancreatic fibroblasts resulted in increased deposition of HA with subsequent decreased K ′ in the ECM (Hammer et al, 2017; Pitarresi et al, 2018). Moreover, the therapeutic implications of this type of approach can be further extended through the incorporation of cancer patient-derived cells or ECM into the appropriate microfluidic system to predict drug response.…”