Biology subjects

Westbrook, T. F.

Publications and source records attributed to Westbrook, T. F..

4 recordsLinked to original sources

bioRxiv2026

Tumor Cell Clustering Enhances Metastatic Competence by Regulating the H3K36 Histone Demethylase KDM2A

Disseminated tumor cells can form clusters via cell-cell adhesion, which increases their capacity to initiate metastasis. Metastatic clusters are characterized by distinct changes in transcription, suggesting that epigenetic mechanisms underlie their unique phenotypic state. By performing functional epigenomic studies in models of non-small cell lung cancer, we identified the histone H3 lysine 36 (H3K36) demethylase KDM2A as being differentially required for the fitness of metastatic cell clusters. This contextual dependency on KDM2A is predicated by tumor cell-cell aggregation, which specifically induces KDM2A binding to CpG island enriched promoters. At these defined genomic loci, KDM2A maintains H3K36 monomethylation, which preferentially correlates with transcriptional activation. KDM2A directly targets oxidative phosphorylation genes and KDM2A activity is required for optimal mitochondrial respiration and apical cell junction integrity in cell clusters. Consequently, suppressing KDM2A reduces metastatic seeding and colonization in multiple organs, including in the brain. These findings reveal a chromatin regulatory mechanism by which homotypic cell communication instructs the epigenome of disseminated tumor cells to potentiate their metastatic competence.

cancer biology↗

bioRxiv2024

An in vivo screen identifies NAT10 as a master regulator of brain metastasis

Metastasis is the major cause of cancer-related deaths. Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis. To better understand the epigenetic regulation of metastasis, we conducted an in vivo shRNA screen for vulnerabilities of brain metastasis and identified N-acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 significantly restrains cancer cell proliferation and migration in vitro, and tumor growth and brain metastasis in vivo. Structure-function analysis of NAT10 showed that its poorly characterized RNA helicase domain is critical for breast cancer cell growth in vitro, while its N-acetyltransferase domain is essential for primary tumor growth and brain metastasis in vivo. Integrative transcriptomic and proteomic analyses revealed key downstream effectors of NAT10, including PHGDH and PSAT1, two catalyzing enzymes for serine biosynthesis implicated in brain metastasis, and HSPA5, known to promote metastasis. We found that distant metastases of breast cancer, especially brain metastases express higher levels of NAT10, PHGDH, PSAT1, and HSPA5. Silencing PHGDH/PSAT1 or HSPA5 in metastatic breast cancer cells inhibits their ability to grow in the serine/glycine-limited condition or migrate, respectively, phenocopying the effects of NAT10 depletion. Moreover, NAT10 promotes the expression of PHGDH, PSAT1, and HSPA5 in its RNA helicase-dependent manner. These findings establish NAT10 as a master regulator of brain metastasis and shed light on the biological functions of its RNA helicase domain, nominating NAT10 as a target for treating metastatic diseases.

cancer biology↗

bioRxiv2022

WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation

Metastatic breast cancer remains a major cause of cancer related deaths in women and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, combination of WDR5-targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.

cancer biology↗

bioRxiv2021

Tumor suppressor PLK2 may serve as a biomarker in triple-negative breast cancer for improved response to PLK1 therapeutics

Polo-like kinase (PLK) family members play important roles in cell cycle regulation. The founding member PLK1 is oncogenic and preclinically validated as a cancer therapeutic target. Paradoxically, PLK2 (chromosome 5q11.2) is frequently deleted in human breast cancers, preferentially in basal-like and triple-negative breast cancer subtypes. Here, we found that PLK2 was tumor suppressive in breast cancer and knockdown of PLK1 rescued phenotypes induced by PLK2-loss both in vitro and in vivo. We also demonstrated that PLK2 directly interacted with PLK1 at prometaphase and that mutations in the kinase domain of PLK2, but not polo-box binding domains, changed their interaction pattern. Furthermore, treatment of syngeneic transplantation mouse tumor models and patient-derived xenografts using the PLK1 inhibitor volasertib alone, or in combination with carboplatin, indicated that PLK2-low breast tumors had a significantly better response to these drugs. Re-expression of PLK2 in an inducible PLK2-null mouse model reduced the therapeutic efficacy of volasertib. Taken together, our data suggest PLK2 loss may serve as a biomarker to predict response to PLK1 therapeutics, alone and in combination with chemotherapy. SignificanceThe tumor suppressive role of PLK2, and its relationship with the oncogene PLK1, provide a mechanistic rationalization to use PLK1 inhibitors in combination with chemotherapy to treat PLK2 low/deleted tumors. TNBC, and other cancers with low PLK2 expression, are such candidates to leverage precision medicine to identify patients who might benefit from treatment with these inhibitors.

cancer biology↗