TGFβ signalling in context Massague, Joan
Nature reviews. Molecular cell biology,
10/2012, Letnik:
13, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has ...been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.
Targeting metastatic cancer Ganesh, Karuna; Massagué, Joan
Nature medicine,
01/2021, Letnik:
27, Številka:
1
Journal Article
Recenzirano
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Despite recent therapeutic advances in cancer treatment, metastasis remains the principal cause of cancer death. Recent work has uncovered the unique biology of metastasis-initiating cells that ...results in tumor growth in distant organs, evasion of immune surveillance and co-option of metastatic microenvironments. Here we review recent progress that is enabling therapeutic advances in treating both micro- and macrometastases. Such insights were gained from cancer sequencing, mechanistic studies and clinical trials, including of immunotherapy. These studies reveal both the origins and nature of metastases and identify new opportunities for developing more effective strategies to target metastatic relapse and improve patient outcomes.
Transforming growth factor (TGF)-β is a crucial enforcer of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Perturbations in TGF-β ...signaling underlie inflammatory diseases and promote tumor emergence. TGF-β is also central to immune suppression within the tumor microenvironment, and recent studies have revealed roles in tumor immune evasion and poor responses to cancer immunotherapy. Here, we present an overview of the complex biology of the TGF-β family and its context-dependent nature. Then, focusing on cancer, we discuss the roles of TGF-β signaling in distinct immune cell types and how this knowledge is being leveraged to unleash the immune system against the tumor.
Massagué and Batlle present an overview of the complex biology of the TGF-β family and, focusing on cancer, discuss the roles of TGF-β signaling in distinct immune cell types and how this knowledge is being leveraged in the clinic.
Metastasis is initiated and sustained through therapy by cancer cells with stem-like and immune-evasive properties, termed metastasis-initiating cells (MIC). Recent progress suggests that MICs result ...from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter slow-cycling states for dormancy, evade immune surveillance, establish supportive interactions with organ-specific niches, and co-opt systemic factors for growth and recurrence after therapy. Mechanistic understanding of the molecular mediators of MIC phenotypes and host tissue ecosystems could yield cancer therapeutics to improve patient outcomes. SIGNIFICANCE: Understanding the origins, traits, and vulnerabilities of progenitor cancer cells with the capacity to initiate metastasis in distant organs, and the host microenvironments that support the ability of these cells to evade immune surveillance and regenerate the tumor, is critical for developing strategies to improve the prevention and treatment of advanced cancer. Leveraging recent progress in our understanding of the metastatic process, here we review the nature of MICs and their ecosystems and offer a perspective on how this knowledge is informing innovative treatments of metastatic cancers.
TGF-β plays a prominent role as an inducer of epithelial-mesenchymal transitions (EMTs) during development and wound healing and in disease conditions such as fibrosis and cancer. During these ...processes EMT occurs together with changes in cell proliferation, differentiation, communication, and extracellular matrix remodeling that are orchestrated by multiple signaling inputs besides TGF-β. Chief among these inputs is RAS-MAPK signaling, which is frequently required for EMT induction by TGF-β. Recent work elucidated the molecular basis for the cooperation between the TGF-β-SMAD and RAS-MAPK pathways in the induction of EMT in embryonic, adult and carcinoma epithelial cells. These studies also provided direct mechanistic links between EMT and progenitor cell differentiation during gastrulation or intra-tumoral fibrosis during cancer metastasis. These insights illuminate the nature of TGF-β driven EMTs as part of broader processes during development, fibrogenesis and metastasis.
Origins of Metastatic Traits Vanharanta, Sakari; Massagué, Joan
Cancer cell,
10/2013, Letnik:
24, Številka:
4
Journal Article
Recenzirano
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How cancer cells acquire the competence to colonize distant organs remains a central question in cancer biology. Tumors can release large numbers of cancer cells into the circulation, but only a ...small proportion of these cells survive on infiltrating distant organs and even fewer form clinically meaningful metastases. During the past decade, many predictive gene signatures and specific mediators of metastasis have been identified, yet how cancer cells acquire these traits has remained obscure. Recent experimental work and high-resolution sequencing of human tissues have started to reveal the molecular and tumor evolutionary principles that underlie the emergence of metastatic traits.
Metastasis is the main cause of death in people with cancer. To colonize distant organs, circulating tumour cells must overcome many obstacles through mechanisms that we are only now starting to ...understand. These include infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds and eventually breaking out to replace the host tissue. They make metastasis a highly inefficient process. However, once metastases have been established, current treatments frequently fail to provide durable responses. An improved understanding of the mechanistic determinants of such colonization is needed to better prevent and treat metastatic cancer.
TGFβ in Cancer Massague, J
Cell,
07/2008, Letnik:
134, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The transforming growth factor β (TGFβ) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFβ exerts ...tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFβ also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFβ response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFβ's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.
Immune checkpoint therapy can induce durable remissions, but many tumors demonstrate resistance. In a recent issue of Nature, Mariathasan et al. (2018) and Tauriello et al. (2018) identify stromal ...TGF-β signaling as a determinant of immune exclusion. Combination TGF-β inhibition and immunotherapy induces complete responses in mouse models.
Immune checkpoint therapy can induce durable remissions, but many tumors demonstrate resistance. In a recent issue of Nature, Mariathasan et al. (2018) and Tauriello et al. (2018) identify stromal TGF-β signaling as a determinant of immune exclusion. Combination TGF-β inhibition and immunotherapy induces complete responses in mouse models.
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