Stromal PTEN Regulates Extracellular Matrix Organization in the Mammary Gland

Abstract

The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing “highways” for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten−/− fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.

The role of collagen in cancer: from bench to bedside

“…These CAFs can even originate from adipose tissue-derived stromal cells [146]. CAFs are classified as tumor-restraining, tumor-promoting, secretory, or ECM-remodeling cells [147], which also exhibit CAF functions via mutated genes [148], the secreted cytokines IL-1β, TNF-α and NF-κB, inflammatory signals, epigenetic regulation, etc. [6].…”

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

“…PTEN genetic inactivation in fibroblasts has extensively been studied in breast cancer [90][91][92].…”

“…The specific deletion of PTEN in murine fibroblasts promotes collagen deposition and parallel alignment of cellular matrix (a feature observed also in patients with breast cancer) even in the absence of cancer cells. Furthermore, PTEN-loss in fibroblasts fosters cancer-associated fibroblasts-like behaviors, such as upregulation of α-smooth muscle actin and MMP activity [92]. Mechanisms of PTEN inactivation have been investigated in pancreatic ductal adenocarcinoma (PDAC), using high throughput techniques.…”

The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

“…Conditional Pten homozygous deletion in the prostate epithelium of castrated mice is reported to loosen areas of surrounding smooth muscle actin and promote collagen deposition, increasing invasive potential [ 356 ]. Interestingly, deletion of Pten in stromal fibroblasts within the murine mammary gland has been shown to initiate significant extracellular matrix (ECM) remodeling, resulting in mammary tumor initiation and invasive progression through alterations in collagen alignments [ 357 , 358 ]. These findings indicate that PTEN can elicit its tumor-suppressive function through stromal fibroblasts and raise the possibility of a similar role in other epithelial cancers.…”