One of the most common sites of breast cancer metastasis is the bone. Current therapeutic interventions remain largely palliative for patients suffering from bone metastases. Our project addresses the urgent need to transform bone metastasis treatment by targeting the MALAT1-TEAD3 axis. MALAT1, one of the few highly conserved nuclear long non-coding RNAs (lncRNAs), is abundantly expressed in normal tissues. Building on our previous finding that MALAT1 suppresses breast cancer metastasis (Kim et al., Nature Genetics 2018), we noted that a specific single nucleotide polymorphism in MALAT1 was associated with low bone density and sought to determine the role of MALAT1 alternations in bone disea...

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One of the most common sites of breast cancer metastasis is the bone. Current therapeutic interventions remain largely palliative for patients suffering from bone metastases. Our project addresses the urgent need to transform bone metastasis treatment by targeting the MALAT1-TEAD3 axis. MALAT1, one of the few highly conserved nuclear long non-coding RNAs (lncRNAs), is abundantly expressed in normal tissues. Building on our previous finding that MALAT1 suppresses breast cancer metastasis (Kim et al., Nature Genetics 2018), we noted that a specific single nucleotide polymorphism in MALAT1 was associated with low bone density and sought to determine the role of MALAT1 alternations in bone diseases. We found that MALAT1 deficiency in mice led to osteoporosis and more severe bone metastases of melanoma and mammary tumor cells, which was reversed when MALAT1 was re-introduced. Single-cell analysis showed that reduced MALAT1 expression in pre-osteoclasts and osteoclasts was associated with osteoporosis and breast cancer metastasis. We further discovered that MALAT1 suppresses osteoclast differentiation by binding and inhibiting TEAD3 (Zhao et al., Nature Communications 2024). Our work revealed the fundamental roles of MALAT1 lncRNA in physiological and pathological processes and suggests that TEAD3 may be a target against osteoporosis and bone metastasis. In future work, we will study the function, elucidate the mechanism of action, and investigate the therapeutic potential of the MALAT1-TEAD3 axis. We will perform preclinical drug testing to determine whether TEAD palmitoylation inhibitors (TEADi, which are well tolerated with durable antitumor responses in ongoing clinical trials) can be used to prevent and treat osteoporosis-associated breast cancer bone metastasis. If successful, TEADi could emerge as drugs that not only elicit antitumor responses through the tumor cell-intrinsic mechanism, but also inhibit bone metastasis through the tumor cell-extrinsic mechanism.

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