Biology subjects

Zong, W.-X.

Publications and source records attributed to Zong, W.-X..

5 recordsLinked to original sources

bioRxiv2026

Loss of PIK3CA allows in vitro growth but not in vivo progression of KRAS mutant lung adenocarcinoma in a syngeneic orthotopic implantation model

Constitutively active KRAS mutations are highly prevalent in lung cancers, but the direct role of its downstream phosphatidylinositol 3-kinase (PI3K) pathway in tumor progression remains unclear. A previous study established the requirement for PIK3CA, the alpha catalytic isoform, in lung tumor development in mouse models with an intact Trp53 tumor suppressor. In this study, we further investigated the requirement for PIK3CA for tumor growth both in vitro and in vivo. We first generated a "KPA" cell line by genetically deleting Pik3ca from a murine lung adenocarcinoma "KP" cell line harboring oncogenic KrasG12D and lacking Trp53. We found that Pik3ca is not required for cell survival and growth in vitro, even under anchorage-independent conditions but reduced the growth rate by 20%. We next orthotopically implanted KP and KPA cells into syngeneic mice and found that PIK3CA is absolutely required for tumor progression, even in the absence of Trp53. Implantation of KP cells, or a "KPS" cell line lacking the Stk11 gene, led to rapid tumor growth and death of all host animals. In contrast, mice implanted with KPA cells all survived with no detectable lung tumors. The gene expression profiles from cultured cell lines suggest KPA cells may be vulnerable to oxidative stress. Indeed, we found KPA cells were more sensitive to hydrogen peroxide and diethyl maleate-induced oxidative stress as compared to KP and KPS cells. Together, these results demonstrate that PIK3CA is not required for lung cancer cell growth induced by mutant KRAS in vitro but is critically needed for in vivo progression and growth.

cancer biology↗

bioRxiv2026

OSTM1 is a ubiquitin E3 ligase that suppresses B-cell malignancy by activating the cAMP/PKA/CREB pathway

Osteoclastogenesis-associated transmembrane protein 1 (OSTM1) is a glycosylated, membrane-integral protein that regulates lysosomal homeostasis, with loss-of-function mutations causing autosomal recessive osteopetrosis. Through a whole-genome CRISPR/Cas9 screen, we identified OSTM1 as a previously unrecognized tumor suppressor in B-cell malignancies. Consistent with this role, OSTM1 is frequently deleted or downregulated across a broad spectrum of human B-cell cancers. In mice, B-cell-specific monoallelic or biallelic ablation of Ostm1 cooperates with Cdkn2a loss to drive lymphomagenesis with near-complete penetrance. Mechanistically, we uncover a cytosolic, non-glycosylated fraction of OSTM1 that functions as a ubiquitin E3 ligase to promote proteasomal degradation of phosphodiesterase 3B (PDE3B). As PDE3B hydrolyzes cAMP and suppresses the tumor-protective PKA/CREB/CREBBP signaling axis, loss of OSTM1 leads to PDE3B stabilization, attenuation of cAMP signaling, and enhanced oncogenic transformation. Together, our findings establish OSTM1 as a critical suppressor of B-cell lymphomagenesis through regulation of the cAMP/PKA/CREB pathway.

cancer biology↗

bioRxiv2025

PTEN-loss confers dependence on the guanylate synthesis enzyme IMPDH in T-cell acute lymphoblastic leukemia

Loss of the tumor suppressor PTEN is common in T-cell acute lymphoblastic leukemia (T-ALL), and is associated with poor prognosis. PTEN-loss drives robust activation of AKT/mTORC1 signaling to promote leukemic cell growth. We find that PTEN-loss in T-ALL confers dependence on the guanylate nucleotide synthesis enzyme inosine 5-monophosphate dehydrogenase (IMPDH) for cell growth and viability. This metabolic vulnerability is dependent on sustained mTORC1 signaling and can be exploited using clinically approved IMPDH inhibitors to selectively kill PTEN-deficient T-ALL cells, and extend survival in genetic and xenograft T-ALL models in mice. Mechanistically, IMPDH inhibitors cause early DNA replication stress, followed by DNA damage. In contrast to treatment with mTORC1 inhibitors, these events culminate in robust and selective cell death in PTEN-deficient T-ALL cells. These findings reveal a targetable metabolic vulnerability in T-ALL, which could provide rationale for repurposing clinically approved IMPDH inhibitors. Statement of SignificanceWe find that the IMPDH inhibitors mycophenolic acid and mizoribine, which are currently used as well-tolerated immunosuppressants, exert anti-leukemic activity in an aggressive molecular subset of T-ALL cells that are associated with poor prognosis. The use of clinically approved compounds to exploit this vulnerability could lead to rapid drug repurposing.

cancer biology↗

bioRxiv2025

Disruption of Mitochondrial Dynamics and Stasis Leads to Liver Injury and Tumorigenesis

Background & AimsMitochondrial dysfunction has been implicated in aging and various cancer development. As highly dynamic organelles, mitochondria constantly undergo fission, mediated by dynamin-related protein 1 (DRP1, gene name Dnm1l), and fusion, regulated by mitofusin 1 (MFN1), MFN2, and optic atrophy 1 (OPA1). However, whether and how dysregulation of mitochondria dynamics would be involved in liver pathogenesis and tumorigenesis is unknown. MethodsDnm1l Flox/Flox (Dnm1lF/F), Mfn1F/F and Mfn2F/F mice were crossed with albumin-Cre mice to generate liver-specific Dnm1l knockout (L-Dnm1l KO), L-Mfn1 KO, L-Mfn2 KO, L-Mfn1, Mfn2 double KO (DKO), and L-Mfn1, Mfn2, Dnm1l triple KO (TKO) mice. These mice were housed for various periods up to 18 months. Some mice also received hydrodynamic tail vein injections of a Sleeping Beauty transposon-transposase plasmid system with c-MYC and YAP. Blood and liver tissues were harvested for biochemical and histological analysis. ResultsL-Dnm1l KO mice had elevated serum alanine aminotransferase levels and increased hepatic fibrosis as early as two months of age. By 12 to 18 months, male L-Dnm1l KO mice developed spontaneous liver tumors, primarily hepatocellular adenomas. While female L-Dnm1l KO mice also developed liver tumors, their incidence was much lower. In contrast, neither L-Mfn1 KO nor L-Mfn2 KO mice had notable liver injury or tumorigenesis. However, a small portion of DKO mice developed tumors at 15-18 month-old. Increased DNA damage, senescence and compensatory proliferation were observed in L-Dnm1l KO mice but were less evident in L-Mfn1 KO, L-Mfn2 KO or DKO mice, indicating that mitochondrial fission is more important to maintain hepatocyte homeostasis and prevent liver tumorigenesis. Interestingly, further deletion of Mfn1 and Mfn2 in L-Dnm1l KO mice markedly abolished liver injury, fibrosis, and both spontaneous and oncogene-induced tumorigenesis. RNA sequencing and metabolomics analysis revealed significant activation of the cGAS-STING-interferon pathway and alterations in the tumor microenvironment pathways, alongside increased pyrimidine synthesis and metabolism in the livers of L-Dnm1l KO mice. Notably, the changes in gene expression and pyrimidine metabolism were considerably corrected in the TKO mice. ConclusionsMitochondrial dynamics and stability are essential for maintaining hepatic mitochondrial homeostasis and hepatocyte functions. Loss of hepatic DRP1 promotes liver tumorigenesis by increasing pyrimidine metabolism and activating the cGAS-STING-mediated innate immune response.

cell biology↗

bioRxiv2023

Propionyl-CoA carboxylase subunit B modulates PIK3CA-regulated immune-surveillance in a pancreatic cancer mouse model

Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca-/- KPC (named KO) cancer cells induces clonal expansion of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using KO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in KO cells (named p-KO) leads to immune evasion, tumor progression and death of host mice. Surprisingly, p-KO tumors are still infiltrated with clonally expanded CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally expanded T cells infiltrating p-KO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.

cancer biology↗