Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

Junhui Hu; Ping Tan; Moe Ishihara; Nicholas A Bayley; Shiruyeh Schokrpur; Jeremy G Reynoso; Yangjun Zhang; Raymond J Lim; Camelia Dumitras; Lu Yang; Steven M Dubinett; Parmjit S Jat; Jacques Van Snick; Jiaoti Huang; Arnold I Chin; Robert M Prins; Thomas G Graeber; Hua Xu; Lily Wu

doi:10.1038/s41392-023-01362-2

Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

Signal Transduct Target Ther. 2023 Apr 17;8(1):155. doi: 10.1038/s41392-023-01362-2.

Authors

Junhui Hu¹, Ping Tan², Moe Ishihara¹, Nicholas A Bayley¹, Shiruyeh Schokrpur³, Jeremy G Reynoso⁴, Yangjun Zhang⁵, Raymond J Lim^{1

6}, Camelia Dumitras^{1

6}, Lu Yang², Steven M Dubinett^{1

6

7}, Parmjit S Jat⁸, Jacques Van Snick⁹, Jiaoti Huang¹⁰, Arnold I Chin^{7

11}, Robert M Prins^{1

4

7}, Thomas G Graeber^{1

7}, Hua Xu^{12

13}, Lily Wu^{14

15

16}

Affiliations

¹ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
² Department of Urology, West China Hospital, Chengdu, China.
³ Department of Hematology and Oncology, University of California San Diego, San Diego, CA, 92103, USA.
⁴ Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Department of Biological Repositories, Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China.
⁶ Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁷ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁸ MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK.
⁹ Ludwig Institute for Cancer Research Ltd, Brussels, Belgium.
¹⁰ Department of Pathology, Duke University, Durham, NC, USA.
¹¹ Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
¹² Department of Biological Repositories, Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China. xu-hua@whu.edu.cn.
¹³ Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei Engineering Research Center, Wuhan, China. xu-hua@whu.edu.cn.
¹⁴ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. lwu@mednet.ucla.edu.
¹⁵ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA. lwu@mednet.ucla.edu.
¹⁶ Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. lwu@mednet.ucla.edu.

Abstract

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL⁺) cells. Renal tumors with either VHL⁺ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL⁺ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL^-) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / pathology
Genes, Tumor Suppressor
Humans
Kidney Neoplasms* / genetics
Kidney Neoplasms* / pathology
Lung Neoplasms* / genetics
Von Hippel-Lindau Tumor Suppressor Protein / genetics

Substances

Von Hippel-Lindau Tumor Suppressor Protein
VHL protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding