Joan Massague

..abstract:..

....

..Mutations in these pathways are the cause of various forms of human cancer and developmental disorders...

..The deconstruction of one of these responses - the cell cycle arrest response - into its elemental molecular parts has shed light into the mechanisms used by tumors to evade surveillance and cause metastasis...

..What are the networks of cell-specific molecules that mould the TGF-beta response to each cell's needs?..

..Our results provide a genome-wide scope of the participation of BRG1 in TGFbeta action and suggest a widespread yet differential involvement of BRG1 SWI/SNF remodeler in the transcriptional response of many genes to this cytokine...

....

..Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGF-beta signal transduction...

..We suggest that the activity of this network confers resistance to TGF-beta-mediated cytostasis during the development of the telencephalic neuroepithelium and in glioblastoma brain tumor cells...

..This co-option of a brain sialyltransferase highlights the role of cell-surface glycosylation in organ-specific metastatic interactions...

..The interplay between linker phosphorylation, Smurf-dependent ubiquitination, and nucleoporin exclusion enables regulation of BMP action by diverse signals and biological contexts...

....

..For a video summary of this article, see the PaperFlick file available with the online Supplemental Data...

..miR-335 and miR-126 are thus identified as metastasis suppressor microRNAs in human breast cancer...

..By inhibiting p21(Cip1) expression Myc favours the initiation of apoptosis, thereby influencing the outcome of a p53 response in favour of cell death...

..As a common target of TGFbeta/Smad signals and stress signals via p38 kinase, ATF3 additionally serves to channel synergy between these pathways in the response of epithelial cells to stress and injury...

..Thus, nuclear CDK8/9 drive a cycle of Smad utilization and disposal that is an integral part of canonical BMP and TGF-beta pathways...

..Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis...

..Thus, Smad2/3-TIF1gamma and Smad2/3-Smad4 function as complementary effector arms in the control of hematopoietic cell fate by the TGFbeta/Smad pathway...

....

..We suggest that C/EBPbeta plays a key role in the coordination of TGFbeta cytostatic gene responses, and its malfunction may trigger evasion of these responses in breast cancer...

..Smad proteins therefore mediate transcriptional activation or repression depending on their associated partners...

..These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche...

..These results argue that induction of Mad expression and Id2 down-regulation are important events during the TGF-beta cytostatic program in epithelial cells...

....

....

..Tumor self-seeding could explain the relationships between anaplasia, tumor size, vascularity and prognosis, and local recurrence seeded by disseminated cells following ostensibly complete tumor excision...

..Others contribute to aggressive growth selectively in the lung. Many encode extracellular proteins and are of previously unknown relevance to cancer metastasis...

..These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations...

..Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity...

..Thus, by directly contacting the nuclear pore complex, Smad2 undergoes constant shuttling, providing a dynamic pool that is competitively drawn by cytoplasmic and nuclear signal transduction partners...

..Both in vivo and in vitro studies indicate that ME exhibits a concentration-dependent inhibitory effect on migration of breast cancer cells...

..In turn, Smad4 increases K18 acetylation to augment TRIM33-Smad2/3 binding. Thus, nodal effectors use the H3K9me3 mark as a platform to switch master regulators of stem cell differentiation from the poised to the active state...

..We suggest that TGF-beta suppresses CTL function in vivo through an anticytotoxic program of transcriptional repression...

..With knowledge cemented in decades of research into tumour-initiating events, current experimental and conceptual models are beginning to address the genetic basis for cancer colonization of distant organs...

..We furthermore identify miR-335 as a robust inhibitor of tumor reinitiation. We thus implicate the miR-335 locus on 7q32.2 as the first selective metastasis suppressor and tumor initiation suppressor locus in human breast cancer...

..These results shed light on the proliferative mechanisms that initiate metastatic colonization, and they implicate Id1 and Id3 as mediators of this malignant function in the TN subgroup of breast cancers...

..The development of TGFbeta inhibitors for clinical use will require a deeper understanding of TGFbeta signaling, its consequences, and the contexts in which it acts...

....

..Our growing understanding of TGFbeta signaling through the Smad pathway provides general principles for how animal cells translate complex inputs into concrete behavior...

..These findings significantly enhance our understanding of breast cancer oncogenesis and aid the development of new prognostic biomarkers for this common malignancy...

..Thus, newly disseminated cancer cells expressing VCAM-1 can thrive in leukocyte-rich microenvironments through juxtacrine activation of a VCAM-1-Ezrin-PI3K/Akt survival pathway...

..Indeed, reframing our understanding of metastasis within the self-seeding model offers new opportunities for prevention and cure of metastatic cancer...

..These results provide important evidence for a transformation-specific interplay between chaperones in regulating apoptosis in malignant cells...

..By integrating the information obtained with these complementary approaches the field is currently obtaining an unprecedented level of understanding of the biology, molecular basis, and therapeutic vulnerabilities of metastasis...

....

..In this issue of Molecular Cell, Groppe et al. (2008) describe the crystal structure of a six-element TGF-beta:receptor complex, addressing long-standing questions about the restrictive nature of this vital receptor interaction...

..The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway...

..Our findings reveal a novel mechanism through which HER2 silences tumor suppression in a concerted manner, contributing to the potency of this oncogene in breast cancer...

..Through this proposed work, we wish to furnish the field with a better understanding of the role of the TGFb/Smad pathway in physiology and a better ability to manage this pathway in tumor progression, metastasis and other disorders. ..