Qianjin Guo

All Publications

• TMEM127 suppresses tumor development by promoting RET ubiquitination, positioning, and degradation. Cell reports Guo, Q., Cheng, Z. M., Gonzalez-Cantú, H., Rotondi, M., Huelgas-Morales, G., Ethiraj, P., Qiu, Z., Lefkowitz, J., Song, W., Landry, B. N., Lopez, H., Estrada-Zuniga, C. M., Goyal, S., Khan, M. A., Walker, T. J., Wang, E., Li, F., Ding, Y., Mulligan, L. M., Aguiar, R. C., Dahia, P. L. 2023; 42 (9): 113070

  Abstract

  The TMEM127 gene encodes a transmembrane protein of poorly known function that is mutated in pheochromocytomas, neural crest-derived tumors of adrenomedullary cells. Here, we report that, at single-nucleus resolution, TMEM127-mutant tumors share precursor cells and transcription regulatory elements with pheochromocytomas carrying mutations of the tyrosine kinase receptor RET. Additionally, TMEM127-mutant pheochromocytomas, human cells, and mouse knockout models of TMEM127 accumulate RET and increase its signaling. TMEM127 contributes to RET cellular positioning, trafficking, and lysosome-mediated degradation. Mechanistically, TMEM127 binds to RET and recruits the NEDD4 E3 ubiquitin ligase for RET ubiquitination and degradation via TMEM127 C-terminal PxxY motifs. Lastly, increased cell proliferation and tumor burden after TMEM127 loss can be reversed by selective RET inhibitors in vitro and in vivo. Our results define TMEM127 as a component of the ubiquitin system and identify aberrant RET stabilization as a likely mechanism through which TMEM127 loss-of-function mutations cause pheochromocytoma.

  View details for DOI 10.1016/j.celrep.2023.113070

  View details for PubMedID 37659079

• A membrane-associated MHC-I inhibitory axis for cancer immune evasion. Cell Chen, X., Lu, Q., Zhou, H., Liu, J., Nadorp, B., Lasry, A., Sun, Z., Lai, B., Rona, G., Zhang, J., Cammer, M., Wang, K., Al-Santli, W., Ciantra, Z., Guo, Q., You, J., Sengupta, D., Boukhris, A., Zhang, H., Liu, C., Cresswell, P., Dahia, P. L., Pagano, M., Aifantis, I., Wang, J. 2023

  Abstract

  Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers, such as acute myeloid leukemia (AML), do not respond or develop resistance. A potential mode of resistance is immune evasion of T cell immunity involving aberrant major histocompatibility complex class I (MHC-I) antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR-Cas9 screens in AML. The top-ranked negative regulators were surface protein sushi domain containing 6 (SUSD6), transmembrane protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SUSD6 forms a trimolecular complex with TMEM127 and MHC-I, which recruits WWP2 for MHC-I ubiquitination and lysosomal degradation. Together with the SUSD6/TMEM127/WWP2 gene signature, which negatively correlates with cancer survival, our findings define a membrane-associated MHC-I inhibitory axis as a potential therapeutic target for both leukemia and solid cancers.

  View details for DOI 10.1016/j.cell.2023.07.016

  View details for PubMedID 37557169

• Loss of Tumour Suppressor TMEM127 Drives RET-mediated Transformation Through Disrupted Membrane Dynamics. bioRxiv : the preprint server for biology Walker, T. J., Reyes-Alvarez, E., Hyndman, B. D., Sugiyama, M. G., Oliveira, L. C., Rekab, A. N., Crupi, M. J., Cabral-Dias, R., Guo, Q., Dahia, P. L., Richardson, D. S., Antonescu, C. N., Mulligan, L. M. 2023

  Abstract

  Internalization from the cell membrane and endosomal trafficking of receptor tyrosine kinases (RTK) are important regulators of signaling in normal cells that can frequently be disrupted in cancer. The adrenal tumour pheochromocytoma (PCC) can be caused by activating mutations of the RET receptor tyrosine kinase, or inactivation of TMEM127, a transmembrane tumour suppressor implicated in trafficking of endosomal cargos. However, the role of aberrant receptor trafficking in PCC is not well understood. Here, we show that loss of TMEM127 causes wildtype RET protein accumulation on the cell surface, where increased receptor density facilitates constitutive ligand-independent activity and downstream signaling, driving cell proliferation. Loss of TMEM127 altered normal cell membrane organization and recruitment and stabilization of membrane protein complexes, impaired assembly, and maturation of clathrin coated pits, and reduced internalization and degradation of cell surface RET. In addition to RTKs, TMEM127 depletion also promoted surface accumulation of several other transmembrane proteins, suggesting it may cause global defects in surface protein activity and function. Together, our data identify TMEM127 as an important determinant of membrane organization, including membrane protein diffusability and protein complex assembly, and provide a novel paradigm for oncogenesis in PCC where altered membrane dynamics promotes cell surface accumulation and constitutive activity of growth factor receptors to drive aberrant signaling and promote transformation.

  View details for DOI 10.1101/2023.06.28.546955

  View details for PubMedID 37425958

  View details for PubMedCentralID PMC10327082

• A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions CELL REPORTS MEDICINE Estrada-Zuniga, C. M., Cheng, Z., Ethiraj, P., Guo, Q., Gonzalez-Cantu, H., Adderley, E., Lopez, H., Landry, B. N., Zainal, A., Aronin, N., Ding, Y., Wang, X., Aguiar, R. T., Dahia, P. M. 2022; 3 (7): 100686

  Abstract

  The RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function; and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy.

  View details for DOI 10.1016/j.xcrm.2022.100686

  View details for Web of Science ID 000839283000004

  View details for PubMedID 35858593

  View details for PubMedCentralID PMC9381411

• Imaging Sarcoplasmic Reticulum Ca2+ Signaling in Intact Cardiac Myocytes CIRCULATION Lu, F., Zhao, Y., Xie, W., Guo, Q., Wang, S., Wang, X., Cheng, H. 2020; 142 (15): 1503-1505

  View details for DOI 10.1161/CIRCULATIONAHA.120.047784

  View details for Web of Science ID 000578286600020

  View details for PubMedID 33044861

• Nanobar Array Assay Revealed Complementary Roles of BIN1 Splice Isoforms in Cardiac T-Tubule Morphogenesis. Nano letters Li, L., Guo, Q., Lou, H., Liang, J., Yang, Y., Xing, X., Li, H., Han, J., Shen, S., Li, H., Ye, H., Di Wu, H., Cui, B., Wang, S. 2020

  Abstract

  Bridging integrator-1 (BIN1) is a family of banana-shaped molecules implicated in cell membrane tubulation. To understand the curvature sensitivity and functional roles of BIN1 splicing isoforms, we engineered vertical nanobars on a cell culture substrate to create high and low curvatures. When expressed individually, BIN1 isoforms with phosphoinositide-binding motifs (pBIN1) appeared preferentially at high-curvature nanobar ends, agreeing well with their membrane tubulation in cardiomyocytes. In contrast, the ubiquitous BIN1 isoform without phosphoinositide-binding motif (uBIN1) exhibited no affinity to membranes around nanobars but accumulated along Z-lines in cardiomyocytes. Importantly, in pBIN1-uBIN1 coexpression, pBIN1 recruited uBIN1 to high-curvature membranes at nanobar ends, and uBIN1 attached the otherwise messy pBIN1 tubules to Z-lines. The complementary cooperation of BIN1 isoforms (comboBIN1) represents a novel mechanism of T-tubule formation along Z-lines in cardiomyocytes. Dysregulation of BIN1 splicing, e.g., during myocardial infarction, underlied T-tubule disorganization, and correction of uBIN1/pBIN1 stoichiometry rescued T-tubule morphology in heart disease.

  View details for DOI 10.1021/acs.nanolett.0c01957

  View details for PubMedID 32787151