Wenqi Wang

The Hippo pathway is a key regulator of development, regeneration, tissue homeostasis, and organ size, and its dysregulation promotes tumorigenesis. However, the precise mechanisms of its regulation in both normal physiology and cancer remain incompletely understood. Here, we identify STK38 and STK38L (also known as NDR1 and NDR2), previously proposed as redundant kinases of LATS, as negative regulators of the Hippo pathway. STK38/L inhibit LATS by competitively binding to MOB1 and disrupting the LATS–MOB1 complex, a process independent of their kinase activity. This inhibitory mechanism is evolutionarily conserved, as the Drosophila ortholog Tricornered similarly impairs Warts–Mats complex formation, resulting in enlarged fly wing size. Pathologically, STK38L is highly expressed in ovarian cancer and required for ovarian tumor growth, and its amplification correlates with YAP activation and increased tumor sensitivity to TEAD inhibitors. Taken together, our study reveals a conserved role of STK38/L in Hippo pathway regulation, providing new insights into Hippo-dependent growth control and cancer development.

Macrophage dysfunction is hallmark of atherosclerotic disease, characterized by inflammation and uptake of oxidized low-density lipoproteins (oxLDL). We investigate the role of the epigenetic reader bromodomain-containing protein 4 (BRD4) in orchestrating macrophage responses through interactions with the mechanosensitive transcriptional coactivators YAP/TAZ. Suppression of BRD4 via bromodomain and extra-terminal motif (BET) protein inhibitors (BETi) unveils a remarkable capacity to mitigate YAP/TAZ-driven inflammation. Knockdown of YAP, TAZ or BRD4 in macrophages shows a significant convergence of inflammatory genes under the regulatory purview of these transcriptional regulators. In addition, persistent activation of YAP and TAZ initiates a partial inflammatory phenotype in macrophages, which is effectively ameliorated with BETi. Notably, CD36 and low-density lipoprotein (LDL) receptor-1 (LOX1), pivotal receptors involved in uptake of oxidized low-density lipoprotein (oxLDL), emerge as direct YAP/TAZ targets. We employed a BD2-specific BETi, ABBV-744, in an AAV-PCSK9-induced atherosclerosis model to test the therapeutic potential of BET inhibition. Although reduction in cholesterol levels is modest, BETi substantially curtails plaque formation, diminishing macrophage infiltration, and suppressing the upregulation of YAP/TAZ and oxLDL uptake receptors associated with atherogenesis. Intriguingly, even in conditions marked by heightened YAP/TAZ expression induced by myeloid cell-targeted YAP/TAZ overexpression, BETi effectively dampens inflammation, mitigates foam cell formation, and disease progression. Our work underscores the considerable promise of targeting the YAP/TAZ-BRD4 axis as a therapeutic strategy for averting atherosclerosis, thereby disrupting the relentless cycle of inflammation, mechanosensory responses, and oxLDL uptake characteristic of atherosclerosis progression.

Motivation: Cancer metastasis is a leading cause of cancer-related deaths, while its underlying mechanisms remain incompletely understood. To colonize distant organs, cancer cells reprogram their metabolism to adapt to diverse environmental challenges. Therefore, elucidating the metabolic pathways that drive cancer metastasis will uncover novel biomarkers and therapeutic targets. Results: We integrated published datasets and systematically analyzed metabolites across multiple cancer cell lines. This large-scale bioinformatic analysis revealed distinct metabolites and metabolic pathways associated with organ-specific metastasis, and underscored the crucial role of tissue of origin in shaping the metabolic landscape of metastatic tumors. Notably, the transsulfuration pathway (also known as the cysteine and methionine metabolism) was strongly enriched in cancer cells with high metastatic potential. We validated this finding in pancreatic cancer, where the pathway enzyme cystathionine β-synthase (CBS) and its metabolic products were highly expressed in metastatic cancer cells. Targeting the transsulfuration pathway either by methionine deprivation or pharmacological inhibition of CBS significantly impaired the migration and invasion of metastatic pancreatic cancer cells. Taken together, our study not only provides a global view of the altered metabolic landscape in metastasis but also identifies the transsulfuration pathway as an oncogenic driver and a therapeutic target for pancreatic cancer metastasis. Availability and implementation: Related data used in this study can be found in the following link: https://github.com/jkyan08/metastasis-associated-metabolic-landscape

The MAP4K family, consisting of seven kinases (MAP4K1–7), plays crucial roles in regulating diverse cellular processes, including proliferation, differentiation, migration and apoptosis. Recent studies have highlighted their involvement in multiple signaling pathways such as mitogen-activated protein kinase, Jun N-terminal kinase and Hippo, implicating them in conditions such as cancer, autoimmune and metabolic disorders and neurodegenerative diseases. Notably, MAP4K proteins have demonstrated significant roles in cancer development and progression, including tumor growth, metastasis and immune modulation. Here we summarize current insights into the roles of individual MAP4K members in cancer and other diseases, emphasizing their distinct and overlapping functions within key signaling networks. Furthermore, we discuss the therapeutic potential of targeting MAP4K family members for cancer treatment. These kinases represent promising targets for developing novel therapies for cancer and related diseases. Future research is essential to clarify the specific molecular mechanisms of MAP4K proteins in cancer and to explore their broader relevance in health and disease.

The platinum-based compounds are widely used in treating various types of cancer through their heavy metal component platinum. However, the development of chemoresistance often limits their clinical effectiveness. In this study, we report the roles of heavy metal response and its associated Hippo pathway in regulating platinum-based chemotherapy. Our data show that the MTF1-dependent heavy metal response induces cancer cell resistance to platinum-based compounds both in vitro and in vivo. This resistance is mitigated by Hippo pathway-mediated phosphorylation of MTF1. Moreover, pharmacological activation of the Hippo pathway sensitizes cancer cells to platinum-based compounds. Clinically, lung adenocarcinoma (LUAD) patients with high MTF1 activity exhibit poor overall survival rates, and Hippo pathway inactivation is positively correlated with elevated MTF1 transcriptional activity in platinum-treated LUAD patients. Collectively, our findings not only unveil a critical role of the Hippo-MTF1 pathway in regulating the response to platinum-based chemotherapy, but also suggest new strategies to enhance its efficacy by targeting the heavy metal response.

The Hippo pathway is commonly altered in cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms. Interestingly, we reveal zinc-finger domain as an integral structure for MOB1 function, whose LOF mutations in head and neck cancer promote tumor growth. Moreover, the schwannoma/meningioma-derived NF2 LOF mutations not only inhibit its tumor suppressive function in the Hippo pathway, but also gain an oncogenic role for NF2 by activating the VANGL-JNK pathway. Collectively, our study not only offers a rich somatic mutation resource for investigating the Hippo pathway in human cancers, but also provides a molecular basis for Hippo-based cancer therapy.

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, that subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer biology and potential therapeutic strategies.