Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin
Jan Attig, … , Charles Swanton, George Kassiotis
Jan Attig, … , Charles Swanton, George Kassiotis
Published May 16, 2023
Citation Information: J Clin Invest. 2023;133(14):e164397. https://doi.org/10.1172/JCI164397.
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Research Article Genetics Oncology

Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin

Abstract

Increased levels and diversity of human endogenous retrovirus (HERV) transcription characterize most cancer types and are linked with disease outcomes. However, the underlying processes are incompletely understood. Here, we show that elevated transcription of HERVH proviruses predicted survival of lung squamous cell carcinoma (LUSC) and identified an isoform of CALB1, encoding calbindin, ectopically driven by an upstream HERVH provirus under the control of KLF5, as the mediator of this effect. HERVH-CALB1 expression was initiated in preinvasive lesions and associated with their progression. Calbindin loss in LUSC cell lines impaired in vitro and in vivo growth and triggered senescence, consistent with a protumor effect. However, calbindin also directly controlled the senescence-associated secretory phenotype (SASP), marked by secretion of CXCL8 and other neutrophil chemoattractants. In established carcinomas, CALB1-negative cancer cells became the dominant source of CXCL8, correlating with neutrophil infiltration and worse prognosis. Thus, HERVH-CALB1 expression in LUSC may display antagonistic pleiotropy, whereby the benefits of escaping senescence early during cancer initiation and clonal competition were offset by the prevention of SASP and protumor inflammation at later stages.

Authors

Jan Attig, Judith Pape, Laura Doglio, Anastasiya Kazachenka, Eleonora Ottina, George R. Young, Katey S.S. Enfield, Iker Valle Aramburu, Kevin W. Ng, Nikhil Faulkner, William Bolland, Venizelos Papayannopoulos, Charles Swanton, George Kassiotis

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Figure 2

HERVH-CALB1 expression promotes cancer cell–intrinsic growth.

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HERVH-CALB1 expression promotes cancer cell–intrinsic growth. (A) CALB1...
(A) CALB1 expression in microarray data (GSE33479) from healthy lung tissue and from the indicated progressive stages preceding LUSC development. (B) CALB1 expression in microarray data (GSE108082) from precancerous lesions that progressed to LUSC (progressive) or spontaneously regressed (regressive). P value calculated with Student’s t test. (C) In vitro doubling times of parental cells and individual calbindin-deficient clones for LK-2 (left) and HARA cells (right). P values calculated with 1-way ANOVA. (D) Liver weights of Rag2–/–Il2rg–/–Cd47–/– recipient mice injected with LK-2 or LK-2 2B7 cells. Symbols represent individual recipient mice from single experiment. P value calculated with Student’s t test. This experiment was repeated 4 times with similar results. (E) H&E staining of liver sections from representative mice in D. Scale bar: 2 mm. (F) Number (left) and overall size (right) of liver nodules in liver section from mice in D. P values calculated with Student’s t test. (G) Tumor growth grades in Rag2–/–Il2rg–/–Cd47–/– recipient mice injected with HARA or HARA 3D5 cells. 0, no tumors detected; 1, tumor growth only in the lung or small liver tumors; 2, extensive tumor growth in lung and liver. Symbols represent individual recipient mice pooled from 3 experiments. P value calculated with χ2 test with Yate’s correction. Uncorrected, P = 0.0021.