Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. Furthermore, after intra-iliac injection, NF1-depleted cells generated significantly greater tumor burden in bone. Transcriptomic profiling revealed enrichment of bone-related gene signatures in NF1-depleted ER+ breast cancer cells, which more potently induced osteoclast differentiation and bone loss in co-culture systems. In parallel, low NF1 expression correlated with repressed T cell functional states in primary breast tumors and bone metastases. Consistent with these clinical observations, NF1-depleted ER+ breast cancer cells more effectively inhibited proliferation, interferon-γ secretion, and cytotoxicity of human primary CD8+ T cells. Collectively, these findings identify NF1 inactivation as a key driver of bone metastasis in a substantial subset of ER+ breast cancers. By amplifying the osteolytic "vicious cycle" and promoting immune evasion, NF1 loss remodels the microenvironment to favor tumor expansion. These results further suggest that NF1 loss functionally links therapy resistance with increased skeletal metastatic potential.

Abstract Prostate cancer is one of the leading causes of cancer-related deaths among men worldwide. Localized prostate tumors in certain patients relapse after surgery, radiation therapy or androgen deprivation therapy (ADT), leading to an aggressive metastatic recurrent disease. We recently found that in prostate cancer patients, SIRT3 (sirtuin 3) expression is significantly decreased in advanced metastatic disease compared to localized tumors. SIRT3 is a mitochondrial deacetylase that modulates the biochemical functions of its substrates by regulating their acetylation status. Restoration of SIRT3 levels in human and mouse prostate tumors reduced prostate cancer progression in both immune-deficient and immune competent animals. Transcriptomic profiling and targeted metabolomics analysis of bulk tumors revealed that SIRT3 regulates one-carbon metabolism pathway by controlling the levels of s-adenosyl methionine (SAM) pools. Mechanistic studies indicated that SIRT3 interacts with the rate limiting enzymes MAT1A and MAT2A that catalyze the conversion of methionine to SAM. Biochemical experiments indicated that SIRT3 deacetylates MAT1A/MAT2A which may contribute towards increased SAM synthesis. Additionally, we found that restoration of SIRT3 levels in prostate tumors increased macrophage reprogramming in the tumor microenvironment of the syngeneic mouse models. These findings provide rationale for our working hypothesis that SIRT3 may modulate prostate tumor-immune microenvironment by regulating one-carbon metabolism, and its loss accelerates lethal prostate cancer progression. Supported by NCI grants: R01CA285707 and R01CA252092 to S.D. Citation Format: Xiaochen Yu, Alphonse Nicholas Dimeck, Eriko Katsuta, Spencer Rosario, Mark Long, Song Liu, Kent Nastiuk, Hai Wang, Subhamoy Dasgupta. Loss of SIRT3 promotes metabolic and epigenetic dysregulation in aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4741.

MALAT1, one of the few highly conserved nuclear long noncoding RNAs (lncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover the fundamental roles of MALAT1 in physiological and pathological processes, we find that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Remarkably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis of melanoma and mammary tumor cells, which can be rescued by genetic add-back of Malat1 . Mechanistically, Malat1 binds to Tead3 protein, a macrophage-osteoclast–specific Tead family member, blocking Tead3 from binding and activating Nfatc1, a master regulator of osteoclastogenesis, which results in the inhibition of Nfatc1-mediated gene transcription and osteoclast differentiation. Notably, single-cell transcriptome analysis of clinical bone samples reveals that reduced MALAT1 expression in pre-osteoclasts and osteoclasts is associated with osteoporosis and metastatic bone lesions. Altogether, these findings identify Malat1 as a lncRNA that protects against osteoporosis and bone metastasis.

2b, in which the micro-CT image used as the representative image for male Malat1-/in Fig. 2a was duplicated and presented as the representative image for the female Malat1+/+ mice.

In breast cancer metastasized to bone, the mineralization of collagen regulates integrin-mediated mechanosignalling, inducing a less proliferative phenotype in breast cancer cells.

MALAT1, one of the few highly conserved nuclear long noncoding RNAs (IncRNAs), is abundantly expressed in normal tissues. Previously, targeted inactivation and genetic rescue experiments identified MALAT1 as a suppressor of breast cancer lung metastasis. On the other hand, Malat1-knockout mice are viable and develop normally. On a quest to discover new roles of MALAT1 in physiological and pathological processes, we found that this lncRNA is downregulated during osteoclastogenesis in humans and mice. Notably, Malat1 deficiency in mice promotes osteoporosis and bone metastasis, which can be rescued by genetic add-back of Malat1. Mechanistically, Malat1 binds to Tead3 protein, a macrophage-osteoclast–specific Tead family member, blocking Tead3 from binding and activating Nfatc1, a master regulator of osteoclastogenesis, which results in the inhibition of Nfatc1-mediated gene transcription and osteoclast differentiation. Altogether, these findings identify Malat1 as a lncRNA that suppresses osteoporosis and bone metastasis.

PDF file - 734K, Figure S1. EGFRvA is widely expressed in various cancer cell lines and tissues. Figure S2. The upregulation of EGFRvA in glioma tissues compared with paired adjacent non-neoplastic brain tissues and a poor prognosis in patients with high-grade gliomas. Figure S3. EGFRvA promotes cell migration and invasion in vitro and in vivo. Figure S4. EGFRvA caused the activation of STAT3 and increased expression of HB-EGF. Figure S5. The positive feedback regulation between HB-EGF and p-STAT3 in EGFRvA-expressing cells. Figure S6. Cell viability and cell adhesion of U87MG EGFRvA cells treated with STAT3 inhibitor AG490, and siRNA-mediated knockdown of STAT3 in U87MG transfectants. Table S1. Clinical characteristics of patients with low or high expression of EGFR or EGFRvA in 52 glioma patients. Table S2. Higher expressed genes in U87MG EGFRvA cells versus U87MG EGFR cells. Table S3. Lower expressed genes in U87MG EGFRvA cells versus U87MG EGFR cells. Table S4. Primers used in this study.

Accumulating evidence from clinical trials indicates chronic hepatitis B virus (HBV) infection is associated with the incidence of diffuse large B-cell lymphoma (DLBCL) and may be associated with the prognosis of DLBCL, though this suggestion remains controversial. We performed a meta-analysis to assess whether HBV infection is associated with prognosis and response to chemotherapy in DLBCL. After a strict literature search strategy, a total of 809 HBV surface antigen (HBsAg) seropositive patients with DLBCL and 2849 HBsAg seronegative patients with DLBCL from twelve trials were included. DLBCL patients with chronic HBV infection had significantly poorer 2- and 5-year overall survival (OS) (HR 1.54, 95% CI 1.23-1.92, P<0.001 and 1.79, 1.48-2.17, P<0.001) and 2- and 5-year progression-free survival (PFS) (HR 1.44, 95% CI 1.14-1.81, P=0.002 and HR 1.34, 95% CI 1.02-1.75, P=0.03). HBsAg-seronegative patients also had a lower complete response (CR) rate (OR 0.48, 95% CI 0.34-0.68, P<0.001), higher progressive disease (PD) rate (OR 2.08, 95% CI 1.34-3.24, P=0.001), and more advanced clinical features. This meta-analysis indicates HBV infection leads to a poorer prognosis and poorer response to standard chemotherapy.

ABSTRACT Osteopetrosis (OMIM: 611497), literally “stone bone,” is a group of inherited bone disorders characterized by increased skeletal mass due to defective osteoclast function. A patient who reported a history of frequent fractures, weakness and fatigue was admitted to our hospital in 2011. The patient presented with the typical features of osteopetrosis: fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in bone mineral density (BMD). Aside from his father's complaint of excessive tooth loss, his mother, two sisters, son, and daughter were healthy. Blood samples of the family members were drawn for genetic analyses. The entire coding region and adjacent splice sites of the pleckstrin homology domain–containing family M (with RUN domain) member 1 (PLEKHM1) gene were sequenced. One mutation, a heterozygous deletion mutation in exon 11 (c.3051_3052delCA), was identified in the patient but not in his relatives. The mutation leads to a translation product with a highly impaired Rubicon homology domain. Co-immunoprecipitation and immunofluorescence analyses using HEK293 cells showed that overexpression of a PLEKHM1 CA-deletion mutant resulted in a dramatic decrease in the interaction between PLEKHM1 and the small GTPase Rab7 compared to wild-type PLEKHM1. The normal processes of endocytosis and autophagy were disturbed in cells expressing the mutant (transfected HEK293 and U937 cells), as indicated by epidermal growth factor receptor (EGFR) degradation and an altered LC3-I/II ratio, respectively, which may lead to a defect in osteoclast function. A four-year follow-up study of the patient showed that the PLEKHM1-dependent osteopetrosis was relatively malignant, with significant symptoms of pancytopenia and hepatosplenomegaly. © 2016 American Society for Bone and Mineral Research.