Biology subjects

Traphagen, N. A.

Publications and source records attributed to Traphagen, N. A..

4 recordsLinked to original sources

bioRxiv2026

Circadian misalignment underlies immune escape in breast cancer

Circadian regulation shapes tissue physiology, yet how it organizes cellular and molecular dynamics within the tumor microenvironment (TME) and influences tumor immunity remains unclear. Using temporal single-nucleus multiomic profiling of mouse breast tumors, we uncovered extensive circadian programs that are both cell-type-specific and shared across the TME, governing proliferation and immune responses. Notably, cancer epithelial cells exhibited global acrophase misalignment relative to immune populations. This intercellular desynchrony manifests as temporal decoupling between tumor proliferation and immune activation, discordant antigen presentation and T cell recognition with intrinsic activation-exhaustion overlap in T cells, and asynchronous PD-1/PD-L1 oscillations that sustain checkpoint-mediated suppression. Similar patterns were observed in human triple-negative breast cancer (TNBC). Together, these findings establish intercellular circadian misalignment as a mechanism of tumor immune evasion and position the circadian architecture of the tumor-immune ecosystem as a previously underappreciated determinant of tumor development and therapeutic response. HIGHLIGHTSO_LISingle-cell multiomics maps circadian regulation of tumor-immune programs. C_LIO_LICircadian regulation in cancer epithelial cells is misaligned with immune cell populations. C_LIO_LITumor-immune temporal misalignment undermines antitumor immunity. C_LIO_LICircadian misalignment in human TNBC suggests relevance for immunotherapy timing. C_LI

cancer biology↗

bioRxiv2025

Lack of synergy between AR targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer

Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous-recombination proficient prostate cancer. STATEMENT OF SIGNIFICANCEAndrogen deprivation does not inhibit DNA repair and does not synergize with PARP inhibition in prostate cancer with intact homologous recombination repair.

cancer biology↗

bioRxiv2023

Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer

PurposeClinical evidence indicates that treatment with estrogens elicits anti-cancer effects in [~]30% of patients with advanced endocrine-resistant estrogen receptor alpha (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains under-utilized. Mechanistic understanding may offer strategies to enhance therapeutic efficacy. Experimental DesignWe performed genome-wide CRISPR/Cas9 screening and transcriptomic profiling in long-term estrogen-deprived (LTED) ER+ breast cancer cells to identify pathways required for therapeutic response to the estrogen 17{beta}-estradiol (E2). We validated findings in cell lines, patient-derived xenografts (PDXs), and patient samples, and developed a novel combination treatment through testing in cell lines and PDX models. ResultsCells treated with E2 exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops). Pharmacological suppression of the DNA damage response via poly(ADP-ribose) polymerase (PARP) inhibition with olaparib enhanced E2-induced DNA damage. PARP inhibition synergized with E2 to suppress growth and prevent tumor recurrence in BRCA1/2-mutant and BRCA1/2-wild-type cell line and PDX models. ConclusionsE2-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells. Inhibition of the DNA damage response using drugs such as PARP inhibitors can enhance therapeutic response to E2. These findings warrant clinical exploration of the combination of E2 with DNA damage response inhibitors in advanced ER+ breast cancer, and suggest that PARP inhibitors may synergize with therapeutics that exacerbate transcriptional stress.

cancer biology↗

bioRxiv2020

AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells

PurposeDespite adjuvant anti-estrogen therapy for patients with estrogen receptor alpha (ER)-positive breast cancer, dormant residual disease can persist for years and eventually cause tumor recurrence. We sought to deduce mechanisms underlying the persistence of dormant cancer cells to identify therapeutic strategies. Experimental DesignMimicking the aromatase inhibitor-induced depletion of estrogen levels used to treat patients, we developed preclinical models of dormancy in ER+ breast cancer induced by estrogen withdrawal in mice. We analyzed tumor xenografts and cultured cancer cells for molecular and cellular responses to estrogen withdrawal and drug treatments. Publicly available clinical breast tumor gene expression datasets were analyzed for responses to neoadjuvant anti-estrogen therapy. ResultsDormant breast cancer cells exhibited upregulated 5 adenosine monophosphate-activated protein kinase (AMPK) levels and activity, and upregulated fatty acid oxidation. While the anti-diabetes AMPK-activating drug metformin slowed the estrogen-driven growth of cells and tumors, metformin promoted the persistence of estrogen-deprived cells and tumors through increased mitochondrial respiration driven by fatty acid oxidation. Pharmacologic or genetic inhibition of AMPK or fatty acid oxidation promoted clearance of dormant residual disease, while dietary fat increased tumor cell survival. ConclusionsAMPK has context-dependent effects in cancer, cautioning against the widespread use of an AMPK activator across disease settings. The development of therapeutics targeting fat metabolism is warranted in ER+ breast cancer. Statement of Translational RelevanceDormant cancer cells that survive adjuvant therapy can ultimately give rise to recurrent/advanced tumors that frequently develop resistance to all approved therapies. Patients with early-stage estrogen receptor alpha (ER)-positive breast cancer are typically treated with surgical resection followed by [≥]5 years of adjuvant anti-estrogen therapy that neutralizes ER and suppresses, but often does not eliminate, tumor-initiating cells. Estrogen withdrawal, which mimics aromatase inhibitor therapy, induced activation of the metabolic sensor 5 adenosine monophosphate-activated protein kinase (AMPK) and upregulated fatty acid oxidation (FAO) in preclinical models. Treatment with the anti-diabetes AMPK-activating drug metformin or high dietary fat intake promoted survival of dormant ER+ breast cancer cells, while anti-anginal drugs that inhibit FAO induced clearance of dormant tumor cells. These findings caution against using AMPK modulators with anti-estrogens in patients with ER+ breast cancer, and warrant testing of FAO inhibitors as anti-cancer agents in combination with anti-estrogens.

cancer biology↗