The tumor microenvironment (TME) has been recognized as an integral component of malignancies in breast and prostate tissues, contributing in confounding ways to tumor progression, metastasis, therapy resistance and disease recurrence. Major components of the TME are immune cells, fibroblasts, pericytes, endothelial cells, mesenchymal stroma/stem cells (MSCs), and extracellular matrix (ECM) components. Herein, we discuss the molecular and cellular heterogeneity within the TME and how this presents unique challenges and opportunities for treating breast and prostate cancers.
Cripto regulates stem cell function in normal and disease contexts via TGFbeta/activin/nodal, PI3K/Akt, MAPK and Wnt signaling. Still, the molecular mechanisms that govern these pleiotropic functions of Cripto remain poorly understood. We performed an unbiased screen for novel Cripto binding proteins using proteomics-based methods, and identified novel proteins including members of myosin II complexes, the actin cytoskeleton, the cellular stress response, and extracellular exosomes. We report that myosin II, and upstream ROCK1/2 activities are required for localization of Cripto to cytoplasm/membrane domains and its subsequent release into the conditioned media fraction of cultured cells. Functionally, we demonstrate that soluble Cripto (one-eyed pinhead in zebrafish) promotes proliferation in mesenchymal stem cells (MSCs) and stem cell-mediated wound healing in the zebrafish caudal fin model of regeneration. Notably, we demonstrate that both Cripto and myosin II inhibitors attenuated regeneration to a similar degree and in a non-additive manner. Taken together, our data present a novel role for myosin II function in regulating subcellular Cripto localization and function in stem cells and an important regulatory mechanism of tissue regeneration. Importantly, these insights may further the development of context-dependent Cripto agonists and antagonists for therapeutic benefit.
It is suggested that the Z-N direct microscopy on its own is the best method (with high specificity) for confirming the diagnosis of acid-fast bacilli. Although the PCR diagnosis of TB appears to be a rapid and sensitive method, the results should be interpreted with care in the clinical settings.
Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor progression and targeted therapy resistance remain poorly understood, presenting significant clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton- and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in SNAI2 expression and enriched for MSC content. Specifically, we identified that the fibroblastic stroma in HER2-positive breast cancer patient tissue stains positive for both nuclear SNAI2 and cytoplasmic PEAK1. Furthermore, mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-positive breast cancer cells in a PEAK1-dependent manner. Analysis of PEAK1-dependent secreted factors from MSCs revealed INHBA/activin-A as a necessary factor in the conditioned media of PEAK1-expressing MSCs that promotes lapatinib resistance. Single-cell CycIF analysis of MSC-breast cancer cell co-cultures identified enrichment of p-Akthigh/p-gH2AXlow, MCL1high/p-gH2AXlow and GRP78high/VIMhigh breast cancer cell subpopulations by the presence of PEAK1-expressing MSCs and lapatinib treatment. Bioinformatic analyses on a PEAK1-centric stroma-tumor cell gene set and follow-up immunostaining of co-cultures predict targeting antiapoptotic and stress pathways as a means to improve targeted therapy responses and patient outcomes in HER2-positive breast cancer and other stroma-rich malignancies. These data provide the first evidence that PEAK1 promotes tumorigenic phenotypes through a previously unrecognized SNAI2-PEAK1-INHBA stromal cell axis.
Cancer is the second leading cause of death in the United States. Mortality in patients with solid, epithelial-derived tumors strongly correlates with disease stage and the systemic metastatic load. In such cancers, notable morphological and molecular changes have been attributed to cells as they pass through a continuum of epithelial-mesenchymal transition (EMT) states and many of these changes are essential for metastasis. While cancer metastasis is a complex cascade that is regulated by cell-autonomous and microenvironmental influences, it is well-accepted that understanding and controlling metastatic disease is a viable method for increasing patient survival. In the past 5 years, the novel non-receptor tyrosine kinase PEAK1 has surfaced as a central regulator of tumor progression and metastasis in the context of solid, epithelial cancers. Here, we review this literature with a special focus on our recent work demonstrating that PEAK1 mediates noncanonical pro-tumorigenic TGFβ signaling and is an intracellular control point between tumor cells and their extracellular microenvironment. We conclude with a brief discussion of potential applications derived from our current understanding of PEAK1 biology.
38Intercellular mechanisms by which the stromal microenvironment contributes to solid tumor 39 progression and targeted therapy resistance remain poorly understood, presenting significant 40 clinical hurdles. PEAK1 (Pseudopodium-Enriched Atypical Kinase One) is an actin cytoskeleton-41 and focal adhesion-associated pseudokinase that promotes cell state plasticity and cancer 42 metastasis by mediating growth factor-integrin signaling crosstalk. Here, we determined that 43 stromal PEAK1 expression predicts poor outcomes in HER2-positive breast cancers high in 44SNAI2 expression and enriched for MSC content. Notably, we identified that mesenchymal stem 45 cells (MSCs) and cancer-associated fibroblasts (CAFs) express high PEAK1 protein levels and 46MSCs require PEAK1 to potentiate tumorigenesis, lapatinib resistance and metastasis of HER2-47 65Cell state plasticity enhances intratumoral heterogeneity and has been shown to be a culprit 66 underlying metastasis, therapy resistance and progression in cancer [1][2][3]. Previous studies have 67 demonstrated a causative relationship between increased stromal tissue content (i.e., 68 desmoplasia), including cancer associated fibroblasts (CAFs) or mesenchymal stem cells 69 (MSCs), in breast cancers and lapatinib resistance or metastasis [4][5][6][7]. In the case of HER2-70 positive breast cancer, where upregulation of the receptor tyrosine kinase HER2 (ErbB2) occurs 71in approximately 20% of all breast malignancies [8], both trastuzumab-and lapatinib-based 72 regimens offer significant clinical benefit [9]. However, a substantial percentage of these tumors 73 display either primary resistance or may be initially sensitive but then adapt to develop acquired 74 resistance [10], and clinical work suggests that patients who progress on lapatinib therapy 75 commonly develop metastatic disease [11]. Importantly, stromal cell non-autonomous 76 mechanisms by which the tumor microenvironment drives lapatinib resistance and/or resistance-77 associated metastasis remain poorly understood. 78Pseudopodium-Enriched Atypical Kinase One (PEAK1 or SGK269) is a cytoskeleton-79 associated pseudokinase [12] and member of the new NFK3 kinase family that has been 80 demonstrated to play key roles in cancer initiation and progression across multiple cancer types 81 including breast [13][14][15], pancreatic [12, 16], lung [17] and colon [12, 18, 19]. Importantly, two 82 other NFK3 kinase family members (SGK223 or Pragmin and PEAK3) have been recently 83 demonstrated to also regulate cancer progression [20, 21]. We previously characterized breast 84 cancer cell autonomous functions of PEAK1 and upstream eIF5A1/2-dependent translation in 85 mediating epithelial-mesenchymal transition (EMT), metastasis and transforming growth factor 86 beta (TGFβ)/fibronectin signaling [13][14][15] 22]. In this regard, PEAK1 has been previously identified 87 as part of the meta-adhesome [23] and a regulator of focal adhesion dynamics [24]. Notably, 88PEAK1 was recently determined to be a core constituent of the fibr...
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.
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