Mengxiong Wang

All Publications

• Analysis of knockout mice reveals critical female-specific roles for the Hippo pathway component PTPN14. Genes & development McCrea, E. M., Makrides, N., Tabata, T., Reineking, W., Vilches-Moure, J. G., Wang, M., Lake, J. S., Vogel, H., Howitt, B., Zhang, X., Attardi, L. D. 2025

  Abstract

  The Hippo pathway regulates many physiological processes, including development, tumor suppression, and wound healing. One understudied Hippo pathway component is PTPN14, an evolutionarily conserved tyrosine phosphatase that inhibits YAP/TAZ. Although it is an established tumor suppressor, PTPN14's role in tissue homeostasis has remained unclear. We thus generated Ptpn14-deficient mice and found that only ∼60% of Ptpn14 -/- mice survived postnatally, highlighting the importance of PTPN14 for viability while also enabling the discovery of PTPN14 physiological functions. Ptpn14 -/- mice developed debilitating corneal lesions and the uterus defect hydrometra, as well as heart and kidney abnormalities. Ptpn14 deficiency precipitated an impaired injury response in the cornea and dysregulated YAP signaling in both the uterus and the cornea. Notably, these phenotypes were female-specific, revealing sexually dimorphic Hippo pathway function through PTPN14. Finally, analysis of human PTPN14 variants suggested that PTPN14's essential roles are conserved in humans, underscoring the importance of our insights for designing therapies to improve women's health.

  View details for DOI 10.1101/gad.352620.125

  View details for PubMedID 40533389

• Integrative multiomic approaches reveal ZMAT3 and p21 as conserved hubs in the p53 tumor suppression network. Cell death and differentiation Boutelle, A. M., Mabene, A. R., Yao, D., Xu, H., Wang, M., Tang, Y. J., Lopez, S. S., Sinha, S., Demeter, J., Cheng, R., Benard, B. A., McCrea, E. M., Valente, L. J., Drainas, A. P., Fischer, M., Majeti, R., Petrov, D. A., Jackson, P. K., Yang, F., Winslow, M. M., Bassik, M. C., Attardi, L. D. 2025

  Abstract

  TP53, the most frequently mutated gene in human cancer, encodes a transcriptional activator that induces myriad downstream target genes. Despite the importance of p53 in tumor suppression, the specific p53 target genes important for tumor suppression remain unclear. Recent studies have identified the p53-inducible gene Zmat3 as a critical effector of tumor suppression, but many questions remain regarding its p53-dependence, activity across contexts, and mechanism of tumor suppression alone and in cooperation with other p53-inducible genes. To address these questions, we used Tuba-seqUltra somatic genome editing and tumor barcoding in a mouse lung adenocarcinoma model, combinatorial in vivo CRISPR/Cas9 screens, meta-analyses of gene expression and Cancer Dependency Map data, and integrative RNA-sequencing and shotgun proteomic analyses. We established Zmat3 as a core component of p53-mediated tumor suppression and identified Cdkn1a as the most potent cooperating p53-induced gene in tumor suppression. We discovered that ZMAT3/CDKN1A serve as near-universal effectors of p53-mediated tumor suppression that regulate cell division, migration, and extracellular matrix organization. Accordingly, combined Zmat3-Cdkn1a inactivation dramatically enhanced cell proliferation and migration compared to controls, akin to p53 inactivation. Together, our findings place ZMAT3 and CDKN1A as hubs of a p53-induced gene program that opposes tumorigenesis across various cellular and genetic contexts.

  View details for DOI 10.1038/s41418-025-01513-8

  View details for PubMedID 40263541

  View details for PubMedCentralID 3927368

• Activating p53Y220C with a Mutant-Specific Small Molecule. bioRxiv : the preprint server for biology Zhu, X., Byun, W. S., Pieńkowska, D. E., Nguyen, K. T., Gerhartz, J., Geng, Q., Qiu, T., Zhong, J., Jiang, Z., Wang, M., Sarott, R. C., Hinshaw, S. M., Zhang, T., Attardi, L. D., Nowak, R. P., Gray, N. S. 2024

  Abstract

  TP53 is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 (TRAP-1) due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription. Treatment of p53Y220C expressing pancreatic cell lines with TRAP-1 results in rapid upregulation of p21 and other p53 target genes and inhibits the growth of p53Y220C-expressing cell lines. Negative control compounds that are unable to form a ternary complex do not have these effects, demonstrating the necessity of chemically induced proximity for the observed pharmacology. This approach to activating mutant p53 highlights how chemically induced proximity can be used to restore the functions of tumor suppressor proteins that have been inactivated by mutation in cancer.

  View details for DOI 10.1101/2024.10.23.619961

  View details for PubMedID 39554093

  View details for PubMedCentralID PMC11565735

• DR5 disulfide bonding functions as a sensor and effector of protein folding stress. Molecular cancer research : MCR Law, M. E., Dulloo, Z. M., Eggleston, S. R., Takacs, G. P., Alexandrow, G. M., Lee, Y. I., Wang, M., Hardy, B., Su, H., Forsyth, B., Das, P., Datta, P. K., Chiang, C. W., Sharma, A., Kanumuri, S. R., Guryanova, O. A., Harrison, J. K., Tirosh, B., Castellano, R. K., Law, B. K. 2024

  Abstract

  New agents are needed that selectively kill cancer cells without harming normal tissues. The TRAIL ligand and its receptors, DR5 and DR4, exhibit cancer-selective toxicity. TRAIL analogs or agonistic antibodies targeting these receptors are available but have not yet received FDA approval for cancer therapy. Small molecules for activating DR5 or DR4 independently of protein ligands may activate TRAIL receptors as a monotherapy or potentiate the efficacy of TRAIL analogs and agonistic antibodies. Previously described Disulfide bond Disrupting Agents (DDAs) activate DR5 by altering its disulfide bonding through inhibition of the Protein Disulfide Isomerases (PDIs) ERp44, AGR2, and PDIA1. Work presented here extends these findings by showing that disruption of single DR5 disulfide bonds causes high-level DR5 expression, disulfide-mediated clustering, and activation of Caspase 8-Caspase 3 mediated pro-apoptotic signaling. Recognition of the extracellular domain of DR5 by various antibodies is strongly influenced by the pattern of DR5 disulfide bonding, which has important implications for the use of agonistic DR5 antibodies for cancer therapy and as research tools. Importantly, other ER stressors, including Thapsigargin and Tunicamycin also alter DR5 disulfide bonding in various cancer cell lines and in some instances, DR5 mis-disulfide bonding is potentiated by overriding the Integrated Stress Response (ISR) with inhibitors of the PERK kinase or the ISR inhibitor ISRIB. These observations indicate that the pattern of DR5 disulfide bonding functions as a sensor of ER stress and serves as an effector of proteotoxic stress by driving extrinsic apoptosis independently of extracellular ligands. Implications: Extreme endoplasmic reticulum stress triggers triage of transmembrane receptor production, whereby mitogenic receptors are downregulated and death receptors are simultaneously elevated.

  View details for DOI 10.1158/1541-7786.MCR-24-0756

  View details for PubMedID 40105733

• p53 governs an AT1 differentiation programme in lung cancer suppression. Nature Kaiser, A. M., Gatto, A., Hanson, K. J., Zhao, R. L., Raj, N., Ozawa, M. G., Seoane, J. A., Bieging-Rolett, K. T., Wang, M., Li, I., Trope, W. L., Liou, D. Z., Shrager, J. B., Plevritis, S. K., Newman, A. M., Van Rechem, C., Attardi, L. D. 2023

  Abstract

  Lung cancer is the leading cause of cancer deaths worldwide1. Mutations in the tumour suppressor gene TP53 occur in 50% of lung adenocarcinomas (LUADs) and are linked to poor prognosis1-4, but how p53 suppresses LUAD development remains enigmatic. We show here that p53 suppresses LUAD by governing cell state, specifically by promoting alveolar type 1 (AT1) differentiation. Using mice that express oncogenic Kras and null, wild-type or hypermorphic Trp53 alleles in alveolar type 2 (AT2) cells, we observed graded effects of p53 on LUAD initiation and progression. RNA sequencing and ATAC sequencing of LUAD cells uncovered a p53-induced AT1 differentiation programme during tumour suppression in vivo through direct DNA binding, chromatin remodelling and induction of genes characteristic of AT1 cells. Single-cell transcriptomics analyses revealed that during LUAD evolution, p53 promotes AT1 differentiation through action in a transitional cell state analogous to a transient intermediary seen during AT2-to-AT1 cell differentiation in alveolar injury repair. Notably, p53 inactivation results in the inappropriate persistence of these transitional cancer cells accompanied by upregulated growth signalling and divergence from lung lineage identity, characteristics associated with LUAD progression. Analysis of Trp53 wild-type and Trp53-null mice showed that p53 also directs alveolar regeneration after injury by regulating AT2 cell self-renewal and promoting transitional cell differentiation into AT1 cells. Collectively, these findings illuminate mechanisms of p53-mediated LUAD suppression, in which p53 governs alveolar differentiation, and suggest that tumour suppression reflects a fundamental role of p53 in orchestrating tissue repair after injury.

  View details for DOI 10.1038/s41586-023-06253-8

  View details for PubMedID 37468633

  View details for PubMedCentralID 4231481

• The Mettl3 epitranscriptomic writer amplifies p53 stress responses. Molecular cell Raj, N., Wang, M., Seoane, J. A., Zhao, R. L., Kaiser, A. M., Moonie, N. A., Demeter, J., Boutelle, A. M., Kerr, C. H., Mulligan, A. S., Moffatt, C., Zeng, S. X., Lu, H., Barna, M., Curtis, C., Chang, H. Y., Jackson, P. K., Attardi, L. D. 2022

  Abstract

  The p53 transcription factor drives anti-proliferative gene expression programs in response to diverse stressors, including DNA damage and oncogenic signaling. Here, we seek to uncover new mechanisms through which p53 regulates gene expression using tandem affinity purification/mass spectrometry to identify p53-interacting proteins. This approach identified METTL3, an m6A RNA-methyltransferase complex (MTC) constituent, as a p53 interactor. We find that METTL3 promotes p53 protein stabilization and target gene expression in response to DNA damage and oncogenic signals, by both catalytic activity-dependent and independent mechanisms. METTL3 also enhances p53 tumor suppressor activity in invivo mouse cancer models and human cancer cells. Notably, METTL3 only promotes tumor suppression in the context of intact p53. Analysis of human cancer genome data further supports the notion that the MTC reinforces p53 function in human cancer. Together, these studies reveal a fundamental role for METTL3 in amplifying p53 signaling in response to cellular stress.

  View details for DOI 10.1016/j.molcel.2022.04.010

  View details for PubMedID 35512709

• A Balancing Act: p53 Activity from Tumor Suppression to Pathology and Therapeutic Implications. Annual review of pathology Wang, M., Attardi, L. D. 2021

  Abstract

  TP53, encoding the p53 transcription factor, is the most frequently mutated tumor suppressor gene across all human cancer types. While p53 has long been appreciated to induce antiproliferative cell cycle arrest, apoptosis, and senescence programs in response to diverse stress signals, various studies in recent years have revealed additional important functions for p53 that likely also contribute to tumor suppression, including roles in regulating tumor metabolism, ferroptosis, signaling in the tumor microenvironment, and stem cell self-renewal/differentiation. Not only does p53 loss or mutation cause cancer, but hyperactive p53 also drives various pathologies, including developmental phenotypes, premature aging, neurodegeneration, and side effects of cancer therapies. These findings underscore the importance of balanced p53 activity and influence our thinking of how to best develop cancer therapies based on modulating the p53 pathway. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  View details for DOI 10.1146/annurev-pathol-042320-025840

  View details for PubMedID 34699262

• Zmat3 Is a Key Splicing Regulator in the p53 Tumor Suppression Program. Molecular cell Bieging-Rolett, K. T., Kaiser, A. M., Morgens, D. W., Boutelle, A. M., Seoane, J. A., Van Nostrand, E. L., Zhu, C., Houlihan, S. L., Mello, S. S., Yee, B. A., McClendon, J., Pierce, S. E., Winters, I. P., Wang, M., Connolly, A. J., Lowe, S. W., Curtis, C., Yeo, G. W., Winslow, M. M., Bassik, M. C., Attardi, L. D. 2020; 80 (3): 452

  Abstract

  Although TP53 is the most commonly mutated gene in human cancers, the p53-dependent transcriptional programs mediating tumor suppression remain incompletely understood. Here, to uncover critical components downstream of p53 in tumor suppression, we perform unbiased RNAi and CRISPR-Cas9-based genetic screens invivo. These screens converge upon the p53-inducible gene Zmat3, encoding an RNA-binding protein, and we demonstrate that ZMAT3 is an important tumor suppressor downstream of p53 in mouse KrasG12D-driven lung and liver cancers and human carcinomas. Integrative analysis of the ZMAT3 RNA-binding landscape and transcriptomic profiling reveals that ZMAT3 directly modulates exon inclusion in transcripts encoding proteins of diverse functions, including the p53 inhibitors MDM4 and MDM2, splicing regulators, and components of varied cellular processes. Interestingly, these exons are enriched in NMD signals, and, accordingly, ZMAT3 broadly affects target transcript stability. Collectively, these studies reveal ZMAT3 as a novel RNA-splicing and homeostasis regulator and a key component of p53-mediated tumor suppression.

  View details for DOI 10.1016/j.molcel.2020.10.022

  View details for PubMedID 33157015

• A novel proteotoxic combination therapy for EGFR+ and HER2+cancers ONCOGENE Wang, M., Ferreira, R. B., Law, M. E., Davis, B. J., Yaaghubi, E., Ghilardi, A. F., Sharma, A., Avery, B. A., Rodriguez, E., Chiang, C., Narayan, S., Heldermon, C. D., Castellano, R. K., Law, B. K. 2019; 38 (22): 4264–82

  Abstract

  While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

  View details for DOI 10.1038/s41388-019-0717-6

  View details for Web of Science ID 000469339100005

  View details for PubMedID 30718919

• The unfolded protein response as a target for anticancer therapeutics CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY Wang, M., Law, M. E., Castellano, R. K., Law, B. K. 2018; 127: 66–79

  Abstract

  The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells, responsible for protein synthesis, folding, sorting, and transportation. ER stress is initiated when the unfolded or misfolded protein load exceeds the capacity of the ER to properly fold protein. Tumor microenvironmental conditions, such as nutrient deprivation, hypoxia, and oxidative stress perturb protein folding and trigger chronic ER stress. Cancer cells can tolerate mild ER stress, however, persistent and severe ER stress kills cancer cells by inducing their autophagy, apoptosis, necroptosis, or immunogenic cell death. Based on this rationale, many drugs have been developed for triggering irremediable ER stress in cancer cells by targeting various processes in the secretory pathway. This review discusses the mechanisms of protein targeting to the ER, the key signaling cassettes that are involved in the ER stress response, and their correlation with cancer formation and progression. Importantly, this review discusses current experimental and FDA approved anti-cancer drugs that induce ER stress, and emerging targets within the secretory pathway for the development of new anticancer drugs.

  View details for DOI 10.1016/j.critrevonc.2018.05.003

  View details for Web of Science ID 000437044500008

  View details for PubMedID 29891114

• Disulfide bond disrupting agents activate the unfolded protein response in EGFR- and HER2-positive breast tumor cells ONCOTARGET Ferreira, R. B., Wang, M., Law, M. E., Davis, B. J., Bartley, A. N., Higgins, P. J., Kilberg, M. S., Santostefano, K. E., Terada, N., Heldermon, C. D., Castellano, R. K., Law, B. K. 2017; 8 (17): 28971–89

  Abstract

  Many breast cancer deaths result from tumors acquiring resistance to available therapies. Thus, new therapeutic agents are needed for targeting drug-resistant breast cancers. Drug-refractory breast cancers include HER2+ tumors that have acquired resistance to HER2-targeted antibodies and kinase inhibitors, and "Triple-Negative" Breast Cancers (TNBCs) that lack the therapeutic targets Estrogen Receptor, Progesterone Receptor, and HER2. A significant fraction of TNBCs overexpress the HER2 family member Epidermal Growth Factor Receptor (EGFR). Thus agents that selectively kill EGFR+ and HER2+ tumors would provide new options for breast cancer therapy. We previously identified a class of compounds we termed Disulfide bond Disrupting Agents (DDAs) that selectively kill EGFR+ and HER2+ breast cancer cells in vitro and blocked the growth of HER2+ breast tumors in an animal model. DDA-dependent cytotoxicity was found to correlate with downregulation of HER1-3 and Akt dephosphorylation. Here we demonstrate that DDAs activate the Unfolded Protein Response (UPR) and that this plays a role in their ability to kill EGFR+ and HER2+ cancer cells. The use of breast cancer cell lines ectopically expressing EGFR or HER2 and pharmacological probes of UPR revealed all three DDA responses: HER1-3 downregulation, Akt dephosphorylation, and UPR activation, contribute to DDA-mediated cytotoxicity. Significantly, EGFR overexpression potentiates each of these responses. Combination studies with DDAs suggest that they may be complementary with EGFR/HER2-specific receptor tyrosine kinase inhibitors and mTORC1 inhibitors to overcome drug resistance.

  View details for DOI 10.18632/oncotarget.15952

  View details for Web of Science ID 000400050000113

  View details for PubMedID 28423644

  View details for PubMedCentralID PMC5438706