Zhewen Xiong

All Publications

• Spontaneous and experimental models of lymph node metastasis. Nature protocols Breuer, C. B., Xiong, Z., Wang, A., Rodriguez, G. E., Abhiraman, G. C., Garcia, K. C., Reticker-Flynn, N. E. 2025

  Abstract

  Lymph node (LN) metastasis is a conserved feature across most solid organ malignancies and portends worse prognoses. Functionally, LN metastases induce systemic tumor-specific immune tolerance and may serve as a reservoir for distant metastases. Nonetheless, there are relatively few preclinical models for interrogating the biology of LN metastasis and its systemic effects at various stages of metastatic progression. We describe a method for modeling LN metastasis of melanoma tumors in mice that enables assessment of tumor and immune cell phenotypes and the functional roles of nodal involvement on distant metastasis. Our model comprises a family of transplantable syngeneic melanoma tumor cell lines evolved to exhibit enhanced LN metastatic potential, which can be used to probe cancer-immune interactions and test new therapeutics. We present both (i) a spontaneous LN metastasis model involving primary tumor implantation and assessment of LN colonization 21-28 d later and (ii) an experimental metastasis model involving implantation of primary tumors followed by direct intra-LN injections of tumor cells. Both models can be extended to assess the impact of LN metastasis on the development of distant metastases through asynchronous intravenous injections of tumors. Finally, we discuss experimental design considerations including when to use spontaneous or experimental models and troubleshooting consistent LN metastasis, making this model accessible for researchers with basic mouse survival-surgery skills. We highlight how LN metastasis models can be used to profile metastatic immune reprogramming, measure the impact of nodal metastases on distant metastases and assess novel anti-metastatic therapeutics.

  View details for DOI 10.1038/s41596-025-01200-5

  View details for PubMedID 40804176

  View details for PubMedCentralID 10511214

• Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma. Gut Xiong, Z., Chan, S. L., Zhou, J., Vong, J. S., Kwong, T. T., Zeng, X., Wu, H., Cao, J., Tu, Y., Feng, Y., Yang, W., Wong, P. P., Si-Tou, W. W., Liu, X., Wang, J., Tang, W., Liang, Z., Lu, J., Li, K. M., Low, J. T., Chan, M. W., Leung, H. H., Chan, A. W., To, K. F., Yip, K. Y., Lo, Y. M., Sung, J. J., Cheng, A. S. 2023; 72 (9): 1758-1773

  Abstract

  Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting.Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481).Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8+ T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8+ T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types.We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.

  View details for DOI 10.1136/gutjnl-2022-328364

  View details for PubMedID 37019619

  View details for PubMedCentralID PMC10423534