Tulpule Lab
Memorial Sloan Kettering Cancer Center
Publications
Highlighted Publications
Tulpule, A*., J. Guan*, D. S. Neel*, H. R. Allegakoen, Y. P. Lin, D. Brown, Y. T. Chou, A. Heslin, N. Chatterjee, S. Perati, S. Menon, T. A. Nguyen, J. Debnath, A. D. Ramirez, X. Shi, B. Yang, S. Feng, S. Makhija, B. Huang and T. G. Bivona (2021). “Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules.” Cell. 2021 May 13;184(10):2649-2664.
Receptor tyrosine kinase (RTK)-mediated activation of downstream effector pathways such as the RAS GTPase/MAP kinase (MAPK) signaling cascade is thought to occur exclusively from lipid membrane compartments in mammalian cells. Here, we uncover a membraneless, protein granule-based subcellular structure that can organize RTK/RAS/MAPK signaling in cancer. Chimeric (fusion) oncoproteins involving certain RTKs including ALK and RET undergo de novo higher-order assembly into membraneless cytoplasmic protein granules that actively signal. These pathogenic biomolecular condensates locally concentrate the RAS activating complex GRB2/SOS1 and activate RAS in a lipid membrane-independent manner. RTK protein granule formation is critical for oncogenic RAS/MAPK signaling output in these cells. We identify a set of protein granule components and establish structural rules that define the formation of membraneless protein granules by RTK oncoproteins. Our findings reveal membraneless, higher-order cytoplasmic protein assembly as a distinct subcellular platform for organizing oncogenic RTK and RAS signaling.
Daniel E. Gracilla, Shruti Menon, Marcus R. Breese, Yone Phar. Lin, Filemon S. Dela Cruz, Tamar Y. Feinberg, Elisa de Stanchina, Ana-Florina Galic, Hannah Allegakoen, Shruthi R. Perati, Nicholas Everin, Teresa Vizconde, Nicholas J. Wen, Ann Heslin, Romel Somwar, Marc Ladanyi, Max Horlbeck, Jonathan S. Weissman, E. Alejandro Sweet-Cordero, Trever G. Bivona, Asmin Tulpule; FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy. Cancer Res 2026; https://doi.org/10.1158/0008-5472.CAN-25-2166
In cancers with genetic loss of specific DNA damage response (DDR) genes (e.g., BRCA1/2 tumor suppressor mutations), synthetic lethal targeting of compensatory DDR pathways has translated into clinical benefit for patients. Whether and how growth-promoting oncogenes might also create tumor-specific vulnerabilities within DDR networks is not well understood. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWSR1::FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET family members are among the earliest factors recruited to DNA double-strand breaks (DSBs), though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. We discover that EWSR1::FLI1 and other FET fusion oncoproteins are recruited to DNA DSBs and impair the activation and downstream signaling of the DNA damage sensor ATM. In multiple FET rearranged cancers, we establish the compensatory ATR signaling axis as a collateral dependency and therapeutic target using patient-derived xenograft models. In summary, we describe how oncogenes can disrupt physiologic DNA repair and provide the preclinical rationale for specifically testing ATR inhibitors in FET rearranged cancers as part of ongoing early phase clinical trials.
