Proactive and reactive roles of TGF-ß in cancer.

Cancer cells adapt to varying stress conditions to survive through plasticity. Stem cells exhibit a high degree of plasticity, allowing them to generate more stem cells or differentiate them into specialized cell types to contribute to tissue development, growth, and repair. Cancer cells can also exhibit plasticity and acquire properties that enhance their survival. TGF-ß is an unrivaled growth factor exploited by cancer cells to gain plasticity. TGF-ß-mediated signaling enables carcinoma cells to alter their epithelial and mesenchymal properties through epithelial-mesenchymal plasticity (EMP). However, TGF-ß is a multifunctional cytokine; thus, the signaling by TGF-ß can be detrimental or beneficial to cancer cells depending on the cellular context. Those cells that overcome the anti-tumor effect of TGF-ß can induce epithelial-mesenchymal transition (EMT) to gain EMP benefits. EMP allows cancer cells to alter their cell properties and the tumor immune microenvironment (TIME), facilitating their survival. Due to the significant roles of TGF-ß and EMP in carcinoma progression, it is essential to understand how TGF-ß enables EMP and how cancer cells exploit this plasticity. This understanding will guide the development of effective TGF-ß-targeting therapies that eliminate cancer cell plasticity.

Spatial and Temporal Relationship between Epithelial-Mesenchymal Transition (EMT) and Stem Cells in Cancer.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is often linked with carcinogenesis. However, EMT is also important for embryo development and only reactivates in cancer. Connecting how EMT occurs during embryonic development and in cancer could help us further understand the root mechanisms of cancer diseases. CONTENT: There are key regulatory elements that contribute to EMT and the induction and maintenance of stem cell properties during embryogenesis, tissue regeneration, and carcinogenesis. Here, we explore the implications of EMT in the different stages of embryogenesis and tissue development. We especially highlight the necessity of EMT in the mesodermal formation and in neural crest cells. Through EMT, these cells gain epithelial-mesenchymal plasticity (EMP). With this transition, crucial morphological changes occur to progress through the metastatic cascade as well as tissue regeneration after an injury. Stem-like cells, including cancer stem cells, are generated from EMT and during this process upregulate factors necessary for stem cell maintenance. Hence, it is important to understand the key regulators allowing stem cell awakening in cancer, which increases plasticity and promotes treatment resistance, to develop strategies targeting this cell population and improve patient outcomes. SUMMARY: EMT involves multifaceted regulation to allow the fluidity needed to facilitate adaptation. This regulatory mechanism, plasticity, involves many cooperating transcription factors. Additionally, posttranslational modifications, such as splicing, activate the correct isoforms for either epithelial or mesenchymal specificity. Moreover, epigenetic regulation also occurs, such as acetylation and methylation. Downstream signaling ultimately results in the EMT which promotes tissue generation/regeneration and cancer progression.

Fibronectin, DHPS and SLC3A2 Signaling Cooperate to Control Tumor Spheroid Growth, Subcellular eIF5A1/2 Distribution and CDK4/6 Inhibitor Resistance.

Extracellular matrix (ECM) protein expression/deposition within and stiffening of the breast cancer microenvironment facilitates disease progression and correlates with poor patient survival. However, the mechanisms by which ECM components control tumorigenic behaviors and responses to therapeutic intervention remain poorly understood. Fibronectin (FN) is a major ECM protein controlling multiple processes. In this regard, we previously reported that DHPS-dependent hypusination of eIF5A1/2 is necessary for fibronectin-mediated breast cancer metastasis and epithelial to mesenchymal transition (EMT). Here, we explored the clinical significance of an interactome generated using hypusination pathway components and markers of intratumoral heterogeneity. Solute carrier 3A2 (SLC3A2 or CD98hc) stood out as an indicator of poor overall survival among patients with basal-like breast cancers that express elevated levels of DHPS. We subsequently discovered that blockade of DHPS or SLC3A2 reduced triple negative breast cancer (TNBC) spheroid growth. Interestingly, spheroids stimulated with exogenous fibronectin were less sensitive to inhibition of either DHPS or SLC3A2 - an effect that could be abrogated by dual DHPS/SLC3A2 blockade. We further discovered that a subset of TNBC cells responded to fibronectin by increasing cytoplasmic localization of eIF5A1/2. Notably, these fibronectin-induced subcellular localization phenotypes correlated with a G0/G1 cell cycle arrest. Fibronectin-treated TNBC cells responded to dual DHPS/SLC3A2 blockade by shifting eIF5A1/2 localization back to a nucleus-dominant state, suppressing proliferation and further arresting cells in the G2/M phase of the cell cycle. Finally, we observed that dual DHPS/SLC3A2 inhibition increased the sensitivity of both Rb-negative and -positive TNBC cells to the CDK4/6 inhibitor palbociclib. Taken together, these data identify a previously unrecognized mechanism through which extracellular fibronectin controls cancer cell tumorigenicity by modulating subcellular eIF5A1/2 localization and provides prognostic/therapeutic utility for targeting the cooperative DHPS/SLC3A2 signaling axis to improve breast cancer treatment responses.

Stabilizing vimentin phosphorylation inhibits stem-like cell properties and metastasis of hybrid epithelial/mesenchymal carcinomas.

Epithelial-mesenchymal transition (EMT) empowers epithelial cells with mesenchymal and stem-like attributes, facilitating metastasis, a leading cause of cancer-related mortality. Hybrid epithelial-mesenchymal (E/M) cells, retaining both epithelial and mesenchymal traits, exhibit heightened metastatic potential and stemness. The mesenchymal intermediate filament, vimentin, is upregulated during EMT, enhancing the resilience and invasiveness of carcinoma cells. The phosphorylation of vimentin is critical to its structure and function. Here, we identify that stabilizing vimentin phosphorylation at serine 56 induces multinucleation, specifically in hybrid E/M cells with stemness properties but not epithelial or mesenchymal cells. Cancer stem-like cells are especially susceptible to vimentin-induced multinucleation relative to differentiated cells, leading to a reduction in self-renewal and stemness. As a result, vimentin-induced multinucleation leads to sustained inhibition of stemness properties, tumor initiation, and metastasis. These observations indicate that a single, targetable phosphorylation event in vimentin is critical for stemness and metastasis in carcinomas with hybrid E/M properties.