Person:
Camargo, Fernando

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Camargo

First Name

Fernando

Name

Camargo, Fernando
Author's Publications: search.filters.isAuthorOfPublication.9966b6a7-7f31-4bb9-8e9f-cbcd00993a95

Search Results

Now showing 1 - 7 of 7
  • No Thumbnail Available
    Publication
    YAP-Dependent Proliferation by a Small Molecule Targeting Annexin A2
    (Springer Science and Business Media LLC, 2021-03-15) Shalhout, Sophia; Yang, Peng-Yu; Grzelak, Edyta M.; Nutsch, Kayla; Shao, Sida; Zambaldo, Claudio; Iaconelli, Jonathan; Ibrahim, Lara; Stanton, Caroline; Chadwick, Stormi R.; Chen, Emily; DeRan, Michael; Li, Sijia; Hull, Mitchell; Wu, Xu; Chatterjee, Arnab K.; Shen, Weijun; Camargo, Fernando; Schultz, Peter; Bollong, Michael J.
    The transcriptional coactivator YAP orchestrates a pro-proliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse upon topical administration of drug. Chemical proteomics revealed the relevant target of PY-60 to be Annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase bound, non-phosphorylated, and transcriptionally active form of YAP. This work reveals ANXA2 to be a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale for promoting YAP-dependent regenerative repair in disease.
  • No Thumbnail Available
    Publication
    A Genetic Screen Identifies an LKB1–MARK Signalling Axis Controlling the Hippo–YAP Pathway
    (Springer Nature, 2014-01) Mohseni, Morvarid; Sun, Jianlong; Lau, Allison; Curtis, Stephen; Goldsmith, Jeffrey; Fox, Victor; Wei, Chongjuan; Frazier, Marsha; Samson, Owen; Wong, Kwok-Kim; Kim, Carla; Camargo, Fernando
    The Hippo-YAP pathway is an emerging signalling cascade involved in the regulation of stem cell activity and organ size. To identify components of this pathway, we performed an RNAi-based kinome screen in human cells. Our screen identified several kinases not previously associated with Hippo signalling that control multiple cellular processes. One of the hits, LKB1, is a common tumour suppressor whose mechanism of action is only partially understood. We demonstrate that LKB1 acts through its substrates of the microtubule affinity-regulating kinase family to regulate the localization of the polarity determinant Scribble and the activity of the core Hippo kinases. Our data also indicate that YAP is functionally important for the tumour suppressive effects of LKB1. Our results identify a signalling axis that links YAP activation with LKB1 mutations, and have implications for the treatment of LKB1-mutant human malignancies. In addition, our findings provide insight into upstream signals of the Hippo-YAP signalling cascade.
  • Thumbnail Image
    Publication
    Restriction of intestinal stem cell expansion and the regenerative response by YAP
    (2012) Barry, Evan R.; Morikawa, Teppei; Butler, Brian L.; Shrestha, Kriti; de la Rosa, Rosemarie; Yan, Kelley S.; Fuchs, Charles; Magness, Scott T.; Smits, Ron; Ogino, Shuji; Kuo, Calvin J.; Camargo, Fernando
    A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signaling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. The mechanisms that counterbalance Wnt-driven proliferation are poorly understood. We demonstrate here that YAP, a protein known for its powerful growth-inducing and oncogenic properties1-2, has an unexpected growth-suppressive function restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells (ISCs) and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signaling independently of the APC/Axin/GSK3β complex partly by limiting the activity of Dishevelled (DVL). DVL signals in the nucleus of ISCs and its forced expression leads to enhanced Wnt signaling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas (CRC) and its expression can restrict the growth of CRC xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.
  • Thumbnail Image
    Publication
    The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation
    (Elsevier BV, 2014) Tremblay, Annie M.; Missiaglia, Edoardo; Galli, Giorgio G.; Hettmer, Simone; Urcia, Roby; Carrara, Matteo; Judson, Rebekah M; Thway, Khin; Nadal, Gema; Selfe, Joanna L.; Murray, Graeme; Calogero, Raffaele A.; De Bari, Cosimo; Zammit, Peter S.; Delorenzi, Mauro; Wagers, Amy; Shipley, Janet; Wackerhage, Henning; Camargo, Fernando
    The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering withMYOD1and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.
  • Thumbnail Image
    Publication
    Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth
    (2016) Cox, Andrew G; Hwang, Katie; Brown, Kristin K.; Evason, Kimberley; Beltz, Sebastian; Tsomides, Allison; O'Connor, Keelin; Galli, Giorgio G.; Yimlamai, Dean; Chhangawala, Sagar; Yuan, Min; Lien, Evan C.; Wucherpfennig, Julia; Nissim, Sahar; Minami, Akihiro; Cohen, David E.; Camargo, Fernando; Asara, John; Houvras, Yariv; Stainier, Didier Y.R.; Goessling, Wolfram
    The Hippo pathway is an important regulator of organ size and tumorigenesis. It is unclear, however, how Hippo signaling provides the cellular building blocks required for rapid growth. Here, we demonstrate that transgenic zebrafish expressing an activated form of the Hippo pathway effector Yap1 (also known as YAP) develop enlarged livers and are prone to liver tumor formation. Transcriptomic and metabolomic profiling identify that Yap1 reprograms glutamine metabolism. Yap1 directly enhances glutamine synthetase (glul) expression and activity, elevating steady-state levels of glutamine and enhancing the relative isotopic enrichment of nitrogen during de novo purine and pyrimidine biosynthesis. Genetic or pharmacological inhibition of GLUL diminishes the isotopic enrichment of nitrogen into nucleotides, suppresses hepatomegaly and the growth of liver cancer cells. Consequently, Yap-driven liver growth is susceptible to nucleotide inhibition. Together, our findings demonstrate that Yap1 integrates the anabolic demands of tissue growth during development and tumorigenesis by reprogramming nitrogen metabolism to stimulate nucleotide biosynthesis.
  • No Thumbnail Available
    Publication
    Live-Animal Imaging of Native Hematopoietic Stem and Progenitor Cells
    (SpringerNature, 2020-02-05) Christodoulou, Constantina; Spencer, Joel; Yeh, Shu-Chi; Turcotte, Raphaele; Kokkaliaris, Konstantinos; Panero, Riccardo; Ramos, Azucena; Guo, Guoji; Seyedhassantehrani, N; Esipova, TV; Vinogradov, SA; Rudzinskas, S; Zhang, Y; Perkins, Archibald; Orkin, Stuart; Calogero, Rafaele; Schroeder, Tim; Lin, Charles; Camargo, Fernando
    The biology of hematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions. Particularly challenging has been the study of dynamic HSC behaviors in the native niche given that live animal HSC tracking under steady state conditions still represents an elusive goal in the field. Here, we describe a dual genetic strategy in mice that restricts reporter labeling to a subset of the most quiescent longterm HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial marrow. We find that this subset of LT-HSCs resides in an endostealsinusoidal niche where they are simultaneously in close proximity to sinusoidal blood vessels and the endosteal surface. In contrast, multipotent progenitor cells (MPPs) display a broader distance distribution from the endosteum and are more likely to be associated with transition zone vessels. Additionally, our results demonstrate that LTHSCs do not occupy the marrow niches with the deepest hypoxia and that they are found in similar hypoxic environments as MPPs. In vivo time-lapse imaging experiments revealed that LT-HSCs display limited motility compared to the more motile MPPs. However, following activation, LT-HSCs become more motile and expand clonally within spatially restricted domains. These spatial domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities exhibiting bone-remodeling activities (resorption and new bone deposition). In contrast, cavities with low bone-resorbing activities do not harbor expanding HSCs. These findings point to a new degree of heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover, which has not been recognized previously. Overall, our work describes a model that enables live imaging of LT-HSCs in the native niche and provides insight into the dynamic behaviors of hematopoietic stem and progenitor cells, and the heterogeneity of HSC niches.
  • No Thumbnail Available
    Publication
    Single-Cell Lineage Tracing Unveils a Role for TCF15 in Haematopoiesis
    (Springer Science and Business Media LLC, 2020-07-15) Rodriguez-Fraticelli, Alejo E.; Weinreb, Caleb; Wang, Shou-Wen; Migueles, Rosa P.; Jankovic, Maja; Usart, Marc; Klein, Allon; Lowell, Sally; Camargo, Fernando
    Bone marrow transplantation therapy relies on the life-long regenerative capacity of haematopoietic stem cells (HSCs). HSCs present a complex variety of regenerative behaviours at the clonal level, but the mechanisms underlying this diversity are still undetermined. Recent advances in single cell RNA sequencing (scRNAseq) have revealed transcriptional differences amongst HSCs, providing a possible explanation for their functional heterogeneity. However, the destructive nature of sequencing assays prevents simultaneous observation of stem cell state and function. To solve this challenge, we implemented expressible lentiviral barcoding, which enabled simultaneous analysis of lineages and transcriptomes from single adult HSCs and their clonal trajectories during long-term bone marrow reconstitution. Differential gene expression analysis between clones with distinct behaviour unveiled an intrinsic molecular signature that characterizes functional long-term repopulating HSCs. Probing this signature through in vivo CRISPR screening, we found the transcription factor Tcf15 to be required, and sufficient, to drive HSC quiescence and long-term self-renewal. In situ, Tcf15 expression labels the most primitive subset of true multipotent HSCs. In conclusion, our work elucidates clone-intrinsic molecular programs associated with functional stem cell heterogeneity, and identifies a mechanism for the maintenance of the self-renewing haematopoietic stem cell state.