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 6

HERVH-CALB1 expression controls cancer cell–intrinsic chemokine production.

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HERVH-CALB1 expression controls cancer cell–intrinsic chemokine product...
(A) Hierarchical clustering of HERVH-CALB1–positive and –negative TCGA LUSC samples (P = 362) according to differential expression (≥2-fold, q < 0.05) of 1,526 genes from Figure 3A is shown here again (top) to indicate the set of 393 genes (boxed) downregulated in HERVH-CALB1–positive compared with HERVH-CALB1–negative samples. Functional annotation by GO of the 393 genes downregulated in HERVH-CALB1–positive samples (bottom). P values calculated with the g:SCS algorithm. (B) Correlation between expression of CALB1 and the indicated chemokine/cytokine or inferred neutrophil proportion in RNA-Seq from TCGA LUSC samples (P = 349). Blue and red colors indicate significant positive and negative correlation, respectively, and gray color indicates lack of significant correlation. (C) t-Distributed stochastic neighbor embedding (t-SNE) clustering of distinct cell types (top) and expression of CALB1 or of the indicated chemokines/cytokines in projections of the same clusters (bottom) determined by analysis of scRNA-Seq data (GSE148071) from representative CALB1-negative and CALB1-positive LUSC tumors. (D) Cancer cell–intrinsic expression of CALB1 and of the indicated chemokines/cytokines in CALB1-negative (P = 10) and CALB1-positive (P = 6) LUSC tumors as in C. Symbols represent tumors from individual patients. P values calculated with Student’s t test. (E) Examples of DNA staining of all cells (DAPI) and of cells with compromised plasma membranes (SYTOX) in human neutrophil cultures incubated over time with supernatants from HARA and HARA 3D5 cells (left). Scale bars: 50 μm. Change in half-life of neutrophils incubated with HARA 3D5 cell supernatants compared with those incubated with HARA cell supernatants (right). Three independent HARA and HARA 3D5 cell culture supernatants were tested, indicated by different symbols. The same symbols are used for separate fields of view of each neutrophil culture. One of 2 experiments is shown. P value calculated with Student’s t test.