RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling

RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribut...

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Published in:	Breast cancer research : BCR Vol. 25; no. 1; p. 74
Main Authors:	Tolg, Cornelia, Milojevic, Maja, Qi, Freda W, Pavanel, Hailie A, Locke, M Elizabeth O, Ma, Jenny, Price, Mathew, Nelson, Andrew C, McCarthy, James B, Hill, Kathleen A, Turley, Eva A
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 22-06-2023 BioMed Central BMC
Subjects:	Agonists Analysis Animals Apoptosis Biological response modifiers Breast cancer Cell cycle Cell migration Cells Colonies CRISPR Disease susceptibility DNA DNA Damage Genes Genetic research Genome editing Genomes Genomics Genotyping HMMR Interferon Lung cancer Lung metastasis Lung Neoplasms - pathology Lungs Mammary Neoplasms, Animal - genetics Metastases Metastasis Mutation Plasmids Positive selection Proteins Reactive Oxygen Species Reagents RHAMM RNA RNA, Small Interfering siRNA Stat1 protein STING Transcriptomes Tumor cells Tumors STING apoptosis Interferon HMMR Lung metastasis RHAMM
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Summary:	RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm-loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. Rhamm-loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm-loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm primary tumor clones that are enriched in lung metastases. Rhamm tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM tumor cells to a significantly greater extent than RHAMM comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1465-542X 1465-5411 1465-542X
DOI:	10.1186/s13058-023-01652-1