Abstract
The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies.
Highlights
The aberrant oncogenic phenotype of tumor cells can revert to a normalized, non-malignant state without necessarily correcting the cancer-driving genomic abnormalities [1,2,3,4,5,6]
Our results demonstrate that misregulation of lipogenic metabolism plays a causal role in progression of malignancy in human breast epithelial cells, and that correction of exacerbated lipogenesis is sufficient to restore a normal-like tissue form and function and suppress tumorigenicity of metastatic breast cancer (BC) cells in vivo
These mutations change the expression of genes involved in proliferation and adhesion, and in signaling pathways such as Wnt and MAPK, as well as the gain of copy-number alterations associated with cancer progression
Summary
The aberrant oncogenic phenotype of tumor cells can revert to a normalized, non-malignant state without necessarily correcting the cancer-driving genomic abnormalities [1,2,3,4,5,6]. Beyond the occurrence of complete remissions in patients with APL treated with ATRA, there have been very few successful attempts at identifying the signaling defects that, once corrected, might successfully favor the process of halting malignancy by overriding the genetic abnormalities in tumor cells. Interest and application of differentiation-based therapy as a viable treatment modality for the clinical management of solid malignancies have lagged mostly due to deficiencies in our understanding of differentiation pathways in solid malignancies. It remains an urgent task of cancer researchers to identify the primary signaling transduction pathways whose normalization would lead to reversions of the malignant phenotype for the most common types of human carcinomas
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
