scispace - formally typeset
Search or ask a question

Showing papers by "Pablo Tamayo published in 2021"


Journal ArticleDOI
William C. Hahn1, Joel S. Bader2, Theodore P. Braun3, Andrea Califano4, Paul A. Clemons5, Brian J. Druker3, Andrew J. Ewald2, Haian Fu6, Subhashini Jagu, Christopher J. Kemp7, William Kim8, Calvin J. Kuo9, Michael T. McManus10, Gordon B. Mills3, Xiulei Mo6, Nidhi Sahni11, Stuart L. Schreiber5, Jessica A. Talamas1, Pablo Tamayo8, Jeffrey W. Tyner3, Bridget K. Wagner5, William A. Weiss10, Daniela S. Gerhard, Vlado Dančík, Shubhroz Gill, Bruce K. Hua, Tanaz Sharifnia, Vasanthi S. Viswanathan, Yilong Zou, Filemon S. Dela Cruz, Andrew L. Kung, Brent R. Stockwell, Jesse S. Boehm, Josh Dempster, Robert T. Manguso, Francisca Vazquez, Lee Cooper, Yuhong Du, Andrey A. Ivanov, Sagar Lonial, Carlos S. Moreno, Qiankun Niu, Taofeek K. Owonikoko, Suresh S. Ramalingam, Matthew A. Reyna, Wei Zhou, Carla Grandori, Ilya Shmulevich, Elizabeth M. Swisher, Jitong Cai, Issac S. Chan, Matthew Dunworth, Yuchen Ge, Dan Georgess, Eloise M. Grasset, Elodie Henriet, Hildur Knutsdottir, Michael G. Lerner, Veena Padmanaban, Matthew C. Perrone, Yasir Suhail, Yohannes Tsehay, Manisha Warrier, Quin Morrow, Tamilla Nechiporuk, Nicola Long, Jennifer Saultz, Andy Kaempf, Jessica Minnier, Cristina E. Tognon, Stephen E. Kurtz, Anupriya Agarwal, Jordana Brown, Kevin Watanabe-Smith, Tania Q. Vu, Thomas Jacob, Yunqi Yan, Bridget Robinson, Evan F. Lind, Yoko Kosaka, Emek Demir, Joseph Estabrook, Michael Grzadkowski, Olga Nikolova, Ken Chen, Ben Deneen, Han Liang, Michael C. Bassik, Asmita Bhattacharya, Kevin C. Brennan, Christina Curtis, Olivier Gevaert, Hanlee P. Ji, Kasper Karlsson, Kremena Karagyozova, Yuan-Hung Lo, Katherine N. Liu, Michitaka Nakano, Anuja Sathe, Amber R. Smith, Kaitlyn Spees, Wing Hing Wong, Kanako Yuki, Matt Hangauer, Dan S. Kaufman, Allan Balmain, Saumya R. Bollam, Wei-Ching Chen, Qi-Wen Fan, Kelly Kersten, Matthew F. Krummel, Yun Rose Li, Marie Menard, Nicole Nasholm, Christin Schmidt, Nina K. Serwas, Hiroyuki Yoda, Alan Ashworth, Sourav Bandyopadhyay, Trevor Bivona, Gabriel Eades, Stefan Oberlin, Neil Tay, Yuhao Wang, Jonathan S. Weissman 
04 Mar 2021-Cell
TL;DR: A framework is described for this expanded list of cancer targets, providing novel opportunities for clinical translation and indicating that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes.

110 citations


Journal ArticleDOI
TL;DR: In this paper, the authors show that epidermal genes including 30% of induced differentiation genes already contain stalled Pol II at the promoters in epidermy stem and progenitor cells which is then released into productive transcription elongation upon differentiation.
Abstract: In adult tissue, stem and progenitor cells must tightly regulate the balance between proliferation and differentiation to sustain homeostasis. How this exquisite balance is achieved is an area of active investigation. Here, we show that epidermal genes, including ~30% of induced differentiation genes already contain stalled Pol II at the promoters in epidermal stem and progenitor cells which is then released into productive transcription elongation upon differentiation. Central to this process are SPT6 and PAF1 which are necessary for the elongation of these differentiation genes. Upon SPT6 or PAF1 depletion there is a loss of human skin differentiation and stratification. Unexpectedly, loss of SPT6 also causes the spontaneous transdifferentiation of epidermal cells into an intestinal-like phenotype due to the stalled transcription of the master regulator of epidermal fate P63. Our findings suggest that control of transcription elongation through SPT6 plays a prominent role in adult somatic tissue differentiation and the inhibition of alternative cell fate choices.

12 citations


Journal ArticleDOI
TL;DR: In this paper, the authors demonstrate that treatment of liver fibrosis with both human iPSC-derived macrophage populations and especially M2 subtype significantly reduces fibrogenic gene expression and disease associated histological markers including Sirius Red, αSMA and desmin in immunodeficient Rag2-/- γc-/- mice model, making this approach a promising cell-based avenue to ameliorate fibrosis.
Abstract: With an increasing number of patients with degenerative hepatic diseases such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metalloproteinases (MMPs) provide an attractive cellular therapy approach. Human induced pluripotent stem cells (iPSCs) are capable of efficiently generating a large-scale, homogenous population of human macrophages using fully defined feeder- and serum-free differentiation protocol. Human iPSC-macrophages exhibit classical surface cell markers and phagocytic activity similar to peripheral blood-derived macrophages. Moreover, gene and cytokine expression analysis reveal that these macrophages can be efficiently polarized to pro-inflammatory M1 or anti-inflammatory M2 phenotypes in presence of LPS + IFN-γ and IL-4 + IL-13, respectively. M1 macrophages express high level of CD80, TNF-α, and IL-6 while M2 macrophages show elevated expression of CD206, CCL17, and CCL22. Here, we demonstrate that treatment of liver fibrosis with both human iPSC-derived macrophage populations and especially M2 subtype significantly reduces fibrogenic gene expression and disease associated histological markers including Sirius Red, αSMA and desmin in immunodeficient Rag2-/- γc-/- mice model, making this approach a promising cell-based avenue to ameliorate fibrosis.

11 citations


Journal ArticleDOI
16 Feb 2021-Cancers
TL;DR: In this article, the authors reported that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients.
Abstract: MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.

11 citations


Journal ArticleDOI
TL;DR: In this article, the authors reported a subpopulation of CD34+KITlow human GIST cells that have intrinsic IM resistance, and these cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34 + KITlow progeny.
Abstract: Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by imatinib (IM), a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST, and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary IM resistance that may represent a reservoir for disease persistence. Here, we report a subpopulation of CD34+KITlow human GIST cells that have intrinsic IM resistance. These cells possess cancer stem cell-like expression profiles and behavior, including self-renewal and differentiation into CD34+KIThigh progeny that are sensitive to IM treatment. We also found that TKI treatment of GIST cell lines led to induction of stem cell-associated transcription factors (OCT4 and NANOG) and concomitant enrichment of the CD34+KITlow cell population. Using a data-driven approach, we constructed a transcriptomic-oncogenic map (Onco-GPS) based on the gene expression of 134 GIST samples to define pathway activation during GIST tumorigenesis. Tumors with low KIT expression had overexpression of cancer stem cell gene signatures consistent with our in vitro findings. Additionally, these tumors had activation of the Gas6/AXL pathway and NF-κB signaling gene signatures. We evaluated these targets in vitro and found that primary IM-resistant GIST cells were effectively targeted with either single-agent bemcentinib (AXL inhibitor) or bardoxolone (NF-κB inhibitor), as well as with either agent in combination with IM. Collectively, these findings suggest that CD34+KITlow cells represent a distinct, but targetable, subpopulation in human GIST that may represent a novel mechanism of primary TKI resistance, as well as a target for overcoming disease persistence following TKI therapy.

6 citations


Journal ArticleDOI
TL;DR: A human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by mRNA expression profiling identified mTOR inhibitors as potential therapeutic agents and TAK228 synergized with carboplatin to inhibit cell growth and induce apoptosis and extended survival in orthotopic xenografts of high-MYC medulloblasts.

4 citations