Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.
ABSTRACT Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express alpha6beta4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail-truncated alpha6beta4 integrin. alpha6beta4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of beta4 integrin is necessary for basal and epidermal growth factor-induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional beta1 and beta4 integrin through activation of NFkappaB, and overexpression of NFkappaB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5-alpha6beta4 integrin-RAC-NFkappaB signaling.
Full-textDOI: · Available from: Valerie M Weaver, May 10, 2015
Click to see the full-text of:
Article: Autocrine laminin-5 ligates alpha6beta4 integrin and activates RAC and NFkappaB to mediate anchorage-independent survival of mammary tumors.
SourceAvailable from: Louis Tong[Show abstract] [Hide abstract]
ABSTRACT: The RhoGTPases, with RhoA, Cdc42 and Rac being major members, are a group of key ubiquitous proteins present in all eukaryotic organisms that subserve such important functions as cell migration, adhesion and differentiation. The nuclear factor kappa (NFκB) is a family of constitutive and inducible transcription factors that through their diverse target genes, play a major roles in processes such as cytokine expression, stress regulation, cell division and transformation. Research over this decade has uncovered new molecular links between the RhoGTPases and the NFκB pathway, with the RhoGTPases playing a positive or negative regulatory role on NFκB activation depending on the context. The RhoA-NFκB has been shown to be important in cytokine activated NFκB processes, such as those induced by TNFα. On the other hand, Rac is important for activating the NFκB response downstream of integrin activation, such as after phagocytosis. Specific residues of Rac1 are important for triggering NFκB activation, and mutations do obliterate this response. Other upstream triggers of the RhoGTPase NFκB interactions include the p120 catenin, with implications for skin inflammation. The networks described here are not only important areas for further research, but are also significant for discovery of targets for translational medicine.Bioscience Reports 05/2014; 34(3). DOI:10.1042/BSR20140021 · 2.85 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Development of a physiologically relevant 3D model system for cancer research and drug development is a current challenge. We have adopted a 3D culture system based on a transglutaminase-crosslinked gelatin gel (Col-Tgel) to mimic the tumor 3D microenvironment. The system has several unique advantages over other alternatives including presenting cell-matrix interaction sites from collagen-derived peptides, geometry-initiated multicellular tumor spheroids, and metabolic gradients in the tumor microenvironment. Also it provides a controllable wide spectrum of gel stiffness for mechanical signals, and technical compatibility with imaging based screening due to its transparent properties. In addition, the Col-Tgel provides a cure-in-situ delivery vehicle for tumor xenograft formation in animals enhancing tumor cell uptake rate. Overall, this distinctive 3D system could offer a platform to more accurately mimic in vivo situations to study tumor formation and progression both in vitro and in vivo.PLoS ONE 08/2014; 9(8):e105616. DOI:10.1371/journal.pone.0105616 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The extracellular matrix regulates tissue development and homeostasis, and its dysregulation contributes to neoplastic progression. The extracellular matrix serves not only as the scaffold upon which tissues are organized but provides critical biochemical and biomechanical cues that direct cell growth, survival, migration and differentiation and modulate vascular development and immune function. Thus, while genetic modifications in tumor cells undoubtedly initiate and drive malignancy, cancer progresses within a dynamically evolving extracellular matrix that modulates virtually every behavioral facet of the tumor cells and cancer-associated stromal cells. Hanahan and Weinberg defined the hallmarks of cancer to encompass key biological capabilities that are acquired and essential for the development, growth and dissemination of all human cancers. These capabilities include sustained proliferation, evasion of growth suppression, death resistance, replicative immortality, induced angiogenesis, initiation of invasion, dysregulation of cellular energetics, avoidance of immune destruction and chronic inflammation. Here, we argue that biophysical and biochemical cues from the tumor-associated extracellular matrix influence each of these cancer hallmarks and are therefore critical for malignancy. We suggest that the success of cancer prevention and therapy programs requires an intimate understanding of the reciprocal feedback between the evolving extracellular matrix, the tumor cells and its cancer-associated cellular stroma.EMBO Reports 11/2014; DOI:10.15252/embr.201439246 · 7.86 Impact Factor