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Oncotarget: Llgl1 prevents metaplastic survival


Here is a link to a video interview with Dr. Joyce Schroeder about this research on the Oncotarget YouTube Channel

Oncotarget published "Llgl1 prevents metaplastic survival driven by epidermal growth factor dependent migration" which reported that We have previously demonstrated that Llgl1 loss results in a gain of mesenchymal phenotypes and a loss of apicobasal and planar polarity.

Cells lacking Llgl1 form mammospheres, where survival and transplantability is dependent upon the Epidermal Growth Factor Receptor.

Additionally, Llgl1 loss allows cells to grow in soft-agar and maintain prolonged survival as orthotopic transplants in NOD-SCIDmice.

The loss of Llgl1 drives EGFR mislocalization and an EGFR mislocalization point mutation drives these same phenotypes, including activation of AKT and TAZ nuclear translocation.

Together, these data in this Oncotarget study indicate that the loss of Llgl1 results in EGFR mislocalization, promoting pre-neoplastic changes.

Dr. Joyce Schroeder from The University of Arizona said, "Epithelial cells are regulated by apicobasal polarity complexes that provide an asymmetric cell structure, regulate growth and survival, migration and invasion, and differentiation."

Advanced metastatic disease is frequently associated with stem cell characteristics, in that both stem cells and highly metastatic cancers exhibit drug resistance, migratory capacity, self-renewal, and the ability to survive and differentiate into new tissues.

In fact, autocrine loops between the EGFR pathway and YAP activation have been identified in ovarian cancer and breast epithelium.

Figure 7: Llgl1 loss promotes cell piling and increased survival in soft agar and mammary fat pads and its expression correlates with increased survival in metastatic breast cancer patients. MCF12A shControl, shLlgl1, shLlgl1 CD44hi/49flo, and shLlgl1CD44lo/49fhi cells were grown (A) on filters, (B and C) in soft agar, or (D) in the mammary fat pads of NOD-SCID mice. A. Cells were grown on transwell filters in normal growth media and probed with anti-GM130 antibody and DAPI. Cells were then imaged on the confocal microscope in the Z plane, arrows indicate polyp formation. B. and C. Cells were plated in soft agar, allowed to grow for 13 days, visualized and enumerated with ImageJ. Representative images (C) are shown beneath quantifications (B). 3 replicates per treatment group, experiment repeated twice. D. 500,000 MCF12A shControl, shLlgl1, shLlgl1 CD44hi/CD49flo, and shLlgl1 CD44lo/CD49fhi cells were suspended in matrigel and injected into the mammary fat pad of NOD-SCID mice. Cell masses were palpated and measured every 3-5 days, shControl n = 3, n = 4 for all other groups. Kaplan-Meier analysis of GSE3494 dataset, (E) N = 236 and (F). N = 234, were analyzed for Llgl1 expression and divided into two groups, top 25% expression levels of Llgl1 and the remaining 75% of lower expression. E. Survival curves show that loss of Llgl1 in breast cancer tumors correlates with lower survival probability. F. Tumor samples were further grouped by elston grades (G1 = grade 1 tumor, G3 = grade 3 tumor) and survival curves for these subgroups are shown (Bottom 75% Llgl1 expression in Grade 3 tumors = dotted green line, top 25% Llgl1 expression in Grade 3 tumors = solid pink line).

One facet of pathway activation is intracellular localization of the receptors, as changes to intracellular localization of EGFR have been shown to play key roles in the activation of signal transduction cascades.

The cell of origin of heterogeneic metastases has been linked to tissue stem cells, cancer stem cells, or transdifferentiating cells.

Of note in this Oncotarget study, TAZ nuclear translocation is known to potentiate EGFR signaling pathways, which in turn can increase CD44 transcription and stem cell characteristics.

In this Oncotarget study, TAZ nuclear translocation is known to potentiate EGFR signaling pathways, which in turn can increase CD44 transcription and stem cell characteristics

The Schroeder Research Team concluded in their Oncotarget Priority Research Paper that We have shown that the loss of Llgl1 also promotes stem-cell like qualities in breast epithelial cells as indicated by the CD44hi/CD49flo/CD24lo expression in MCF12A cells.

In an attempt to address the role of Llgl1 in tumor progression, we transfected an Llgl1-GFP construct into breast cancer cell lines with little to no Llgl1 expression, including MDA-MB-453, MDA-MB-231, and T47D.

In each case, these cell lines died within 72 hours of transfection with Llgl1, which prevented us from performing any long term cell growth or transplant experiments.

Llgl1's role as a polarity regulator in the Scribble complex is important, and as we have shown, its loss results in an increase of cancer stem-cell like qualities, migration, and transplant survival in an EGF-dependent manner.

Our data shows that Llgl1 is a necessary regulator in the prevention of metaplasia and that its loss results in multiple aberrant characteristics, all of which can decrease patient survival, warranting further exploration of Llgl1 as a tumor suppressor and potential therapeutic target.

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DOI - https://doi.org/10.18632/oncotarget.11320

Full text - https://www.oncotarget.com/article/11320/text/

Correspondence to - Joyce Schroeder - joyces@email.arizona.edu

Keywords - polarity, migration, Llgl1, epidermal growth factor receptor, TAZ

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