Biology subjects

Koliavas, S.

Publications and source records attributed to Koliavas, S..

3 recordsLinked to original sources

bioRxiv2026

Targeting wild type NTRK decreases brain metastases of lung cancers non-driven by NTRK fusions

The central nervous system (CNS) is a common site of metastatic spread for both non-small cell and small cell lung cancer, yet the therapeutic strategies to prevent and decrease lung cancer brain metastases remain limited. Tyrosine kinase inhibitors have shown promising results in increasing the overall response in brain metastases, owing to their brain penetrance and increased effectiveness; however, their use is limited to the small group of tumors carrying specific oncogenic drivers. Among these, inhibitors with activity against neurotrophic tyrosine receptor kinases (NTRKs) are showing promising effects in reducing CNS metastases in cancers driven by gene rearrangements of these drugs targets. However, wild-type NTRKs are susceptible to activation by their canonical ligands, which are expressed throughout the brain metastatic niche and can, in a paracrine manner, activate NTRK function in cancer cells. Here we show that NTRKs are expressed in primary tumors, brain metastases, and lung cancer cells with various driver mutations expressing wild-type NTRK2 (WT-TrkB). We demonstrate that WT-TrkB activates downstream signaling and proliferation in response to exogenous BDNF and conditioned media from reactive astrocytes known to secrete BDNF in the brain niche. Importantly, the FDA-approved NTRK inhibitor entrectinib blocked BDNF and astrocyte-induced survival pathways in multiple lung cancer cell lines, decreased their proliferation in vitro, and effectively prevented brain metastatic colonization and progression in vivo without significant effects on extracranial disease. Thus, these studies suggest that brain-dependent activation of NTRK is critical for brain metastases of WT-NTRK+ lung cancers, and therefore, NTRK inhibitors can be used to target non-fusion NTRK function to prevent or decrease brain metastases. SIGNIFICANCEThese studies demonstrate that NTRK wild-type receptors are important drivers of brain metastatic colonization and progression in different subtypes of lung cancer, independent of their driver alterations. Thus, they provide rationale to expand the use of FDA-approved NTRK inhibitors with brain penetrance for the prevention of CNS metastases.

cancer biology↗

bioRxiv2026

Estradiol Reprograms Microglia to Create an Immune-Suppressed Niche Permissive to Breast Cancer Brain Metastasis

BackgroundYoung age is an independent risk factor for the development of breast cancer brain metastases (BM). Prior work showed that 17{beta}-estradiol (E2), the predominant premenopausal hormone, promotes BM of tumors intrinsically unresponsive to E2, in part through modulating estrogen receptor-alpha expressing (ER) glial cells. However, how E2 reshapes the brain tumor microenvironment (TME), particularly microglia-mediated immunity, and its impact to BM progression remains unclear. MethodsscRNA sequencing and multiparametric flow cytometry were used to define the impact of E2 and E2-suppression on brain immune-cell populations across different stages of BM progression using spontaneous and experimental models of BM. Depletion of microglia and T cell co-cultures were used to study microglias role in E2-induced BM. The effects of E2-suppression alone or in combination with whole brain radiotherapy were tested in preclinical models mimicking late-stage BM. ResultsE2 repressed immune surveillance and immune activation programs in microglia from early to late stages of brain metastatic progression, suppressing recruitment of effector immune cells to BM. Estrogen suppression, in turn reactivated anti-tumoral signaling in microglia and increased recruitment of effector immune cells to the brain. Microglia from E2-stimulated BM-bearing mice showed decreased ability to induce interferon cytotoxic function and expansion of activated T cells. Conversely, E2-suppression reactivated an effective anti-tumoral response and synergized with RT to significantly decrease BM progression. ConclusionThese findings reveal a previously unrecognized mechanism by which E2 accelerates BC-BM progression through microglial immunosuppression and support evaluation of endocrine therapies as adjunct treatments for ER- brain metastases. Importance of the StudyStandard of care for BM includes stereotactic radiosurgery (SRS) alone or in combination with surgery, systemic chemotherapy or targeted therapies. Our studies show that ovariectomy (which eliminates ovarian E2) and aromatase inhibitors (AIs, which eliminate peripheral E2 synthesis) reduce progression of BM when used in combination with WBRT and in immuno-competent models. We demonstrate E2 promotes an immunosuppressive brain microenvironment from early stages of metastatic progression, in part through modulation of myeloid cells and repression of recruitment of effector T cells to the brain. Thus, these studies suggest that FDA-approved E2-depletion therapies (aromatase inhibitors and selective-estrogen modulators) could be used in combination with brain irradiation to decrease BM progression.

cancer biology↗

bioRxiv2025

Brain FGF2 and NCAM1 contribute to FGFR1-dependent progression of ER+ breast cancer brain metastases in young and aged hosts

Estrogen receptor positive (ER+) breast cancer represents a significant proportion of breast cancer brain metastasis but remains understudied. Here, we report that FGFR1-amplification, a well-established driver of ER+ breast cancer endocrine resistance, promotes ER+ breast cancer brain metastatic colonization in young and aged female mice, through both canonical FGF2/FGFR1 signaling and non-canonical NCAM1/FGFR1 interactions. Astrocytic FGF2-mediated paracrine activation of FGFR1 promoted breast cancer brain metastasis in estrogen-treated young mice, but FGF2 levels and signaling decreased in the brain with aging and estrogen-depletion. Neuronal and astrocytic NCAM1, which remain unchanged in young and aged brains, promoted adhesion to neurons, migration, and growth of ER+ cells, suggesting that interactions with astrocytes and neurons facilitate early ER+ breast cancer brain metastasis colonization through FGFR1. Importantly, FDA-approved FGFR inhibitors effectively blocked early colonization but not late-stage brain metastases, suggesting prevention of FGFR1+ brain metastases as a window of opportunity for FGFR1 inhibitors.

cancer biology↗