Studying Cell Polarity Dynamics During Cancer Initiation Using Inducible 3D Organotypic Cultures

Catterall, Rachel; Kurdieh, Reem; McCaffrey, Luke

doi:10.1007/978-1-0716-2035-9_26

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…3D organotypic cultures were prepared as described elsewhere ( 30 , 82 ). Briefly, mammary glands from 8- to 12-week-old mice were dissociated in 10 mL DMEM/F12, 1× penicillin/streptomycin, 50 mg/mL gentamycin (Wisent, 450-135-XL), and 2 mg/mL collagenase B (Roche, 11088831001) for 1 hour at 37°C, and then washed in PBS with 5% FBS (Wisent, 080-150), centrifuged at 1,500 g for 15 seconds, and resuspended in 0.25% trypsin (Wisent, 325-143-ES) for 20 minutes at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…To examine tumor initiating events further and provide a tractable system for molecular analysis, we established three-dimensional (3D) organotypic cultures (32) from MIC/c-Src +/+ and MIC/c-Src L/L mammary epithelia (Supplemental Figure 2D). Following induction of the MIC transgene, wild-type organoids formed solid structures with a collapsed lumen and epithelial stratification, while c-Src deficient organoids were smaller with an intact lumen (Figure 2B) and retained membrane localization of the adherens junction marker E-Cadherin and the tight junction marker ZO-1, both of which were mislocalized in MIC/c-Src +/+ organoids (Figure 2B, Supplemental Figure 2E).…”

Section: Loss Of C-src Function Blocks Early Breast Cancer Progressionmentioning

confidence: 99%

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Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Nandi¹,

Smith²,

Sanguin-Gendreau³

et al. 2023

Journal of Clinical Investigation

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Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcome, yet the underlying mechanisms are incompletely understood. Here, we have shown that deleting c-Src in a genetically engineered model mimicking the Luminal B molecular subtype of breast cancer abrogates the activity of Forkhead Box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylates FOXM1 on two tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2-M cell cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of Luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2-M cell cycle arrest and apoptosis, blocked tumor progression and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and showed that the expression of FOXM1 target genes predicts poor outcome and associates with the Luminal B subtype, which responds poorly to approved therapies. These findings have revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.

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Section: Methodsmentioning

confidence: 99%

Section: Loss Of C-src Function Blocks Early Breast Cancer Progressionmentioning

confidence: 99%

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Nandi¹,

Smith²,

Sanguin-Gendreau³

et al. 2023

Journal of Clinical Investigation

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“…[ 5 ]. Abnormal cell polarity may lead to developmental abnormalities, severe birth defects, or tumorigenesis [ 6 , 7 , 8 , 9 ]. Disrupted cell polarity is considered a hallmark of human cancer [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Expression, Prognostic Value, and Functional Mechanism of Polarity-Related Genes in Hepatocellular Carcinoma

Zhu

Zhang

Ouyang

et al. 2022

IJMS

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Hepatocellular carcinoma (HCC) is a common malignant tumor with high mortality and poor prognoses around the world. Within-cell polarity is crucial to cell development and function maintenance, and some studies have found that it is closely related to cancer initiation, metastasis, and prognosis. The aim of our research was to find polarity-related biomarkers which improve the treatment and prognosis of HCC. For the knowledge-driven analysis, 189 polarity-related genes (PRGs) were retrieved and curated manually from the molecular signatures database and reviews. Meanwhile, in the data-driven part, genomic datasets and clinical records of HCC was obtained from the cancer genome atlas database. The potential candidates were considered in the respect to differential expression, mutation rate, and prognostic value. Sixty-one PRGs that passed the knowledge and data-driven screening were applied for function analysis and mechanism deduction. Elastic net model combing least absolute shrinkage and selection operator and ridge regression analysis refined the input into a 12-PRG risk model, and its pharmaceutical potency was evaluated. These findings demonstrated that the integration of multi-omics of PRGs can help us in untangling the liver cancer pathogenesis as well as illustrate the underlying mechanisms and therapeutic targets.

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A Tumor Accelerator Based on Multicomponent Bone Scaffolds and Cancer Cell Homing

et al. 2022

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Bone tissue attracts cancer cell homing biologically, mechanically, or chemically. It is difficult and time consuming to identify their complex cross-talk using existed methods. In this study, a multi-component bone matrix was fabricated using gelatin, hydroxyapatite (HAp), and epidermal growth factor (EGF) as raw materials to investigate how “acellular” bone matrix affects cancer cell homing in bone. Then, EGF-responsive cancer cells were cultured with the scaffold in a dynamical bioreactor. For different culture periods, the effects of HAp, gelatin, and EGF on the cell adhesion, proliferation, 3D growth, and migration of cancer were evaluated. The results indicated that a small amount of calcium ion released from the scaffolds accelerated cancer MDA-MB-231 adhesion on the surface of inner pores. Moreover, degradable gelatin key caused cancer cell growth on the scaffold surface to turn into a 3D aggregation. Despite this, the formation of cancer spheroids was slow, and required 14 days of dynamic culture. Thankfully, EGF promoted cancer cell adhesion, proliferation, and migration, and cancer spheroids were observed only after 3-day culture. We concluded that the combination of the multiple components in this scaffold allows cancer cells to meet multiple requirements of cancer dynamic progression.

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Studying Cell Polarity Dynamics During Cancer Initiation Using Inducible 3D Organotypic Cultures

Cited by 3 publications

References 20 publications

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression

Expression, Prognostic Value, and Functional Mechanism of Polarity-Related Genes in Hepatocellular Carcinoma

A Tumor Accelerator Based on Multicomponent Bone Scaffolds and Cancer Cell Homing

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