Biology subjects

Lindquist, J.

Publications and source records attributed to Lindquist, J..

3 recordsLinked to original sources

bioRxiv2026

DNA Polymerase Beta Catalytic and Fidelity Mutations Drive Platinum Specific Drug Sensitivity

With the advent of genome sequencing and its widespread use in the clinic, there is a great need to identify mutational biomarkers that predict therapeutic responses. DNA polymerase Beta (Pol{beta}) and the base excision repair (BER) pathway have been previously implicated as modulators of response to platinum-based chemotherapies and are mutated in as high as 30% of cancers. Here, we show in a triple-negative breast cancer (TNBC) model that two classes of mutations in Pol{beta}, reduced catalytic activity (E295K and D256A mutation) and reduced fidelity (I260M), are sufficient to drive cisplatin and carboplatin-specific sensitivity. Cellular response to oxaliplatin in these Pol{beta} mutant models is minimal relative to cisplatin and carboplatin. Additionally, we show that sensitivity is associated with reduced repair of both platinum-induced DNA intrastrand adducts and interstrand crosslinks (ICLs). Downregulation of the upstream BER factor uracil DNA glycosylase (UNG) reverses drug sensitivity consistent with these Pol{beta} mutations negatively impacting ICL DNA repair to drive drug sensitivity. In addition, intrastrand adduct repair readout indicates these lesions also play a role in the sensitivity observed in Pol{beta} mutant models. In vivo studies demonstrate a significant effect on tumor growth delay with cisplatin treatment in tumor xenografts harboring Pol{beta} mutations. These results support the potential for using Pol{beta} mutations as predictive biomarkers for cisplatin and carboplatin therapies in the clinical setting.

Cancer Biology↗

bioRxiv2026

DNMT mRNA stability and YB-1 cooperatively regulate ABCB1 to drive cisplatin chemoresistance in cholangiocarcinoma

Background and AimsIntrahepatic cholangiocarcinoma (iCCA) is a tumor type with a high lethality due to late diagnosis and profound resistance to conventional chemotherapy. To date the molecular mechanisms underlying multidrug resistance remain poorly defined. Here, we integrate single-cell transcriptomics, clinicopathological analysis, and functional genomics to elucidate the molecular basis of cisplatin resistance in iCCA. Approach and ResultsSingle-cell RNA sequencing of iCCA and adjacent liver tissues revealed pronounced expression of Y-box-binding protein 1 (YB-1) in aneuploid malignant cholangiocarcinoma cells, with YB-1 expression progressively increasing during malignant evolution and strongly associated with chemoresistance. Clinically, elevated YB-1 expression-particularly its nuclear localization-robustly predicts poor overall survival and chemotherapy failure in patients with iCCA. Mechanistically, we demonstrate that cisplatin induces phosphorylation-dependent nuclear translocation of YB-1, enabling direct transcriptional activation of the drug efflux transporter ABCB1. Importantly, this process requires ABCB1 promoter demethylation, which is driven by cisplatin-induced, mA-dependent destabilization of DNMT1 and DNMT3B mRNAs. This destabilization occurs through disruption of the YB-1-IGF2BP1/3-DNMT mRNA stabilizing complex and subsequent recruitment of DNMT transcripts to YTHDF2-mediated processing bodies for degradation. ConclusionsOur findings uncover a previously unrecognized YB-1-mA-DNMT regulatory axis that drives chemotherapeutic resistance in iCCA, highlighting YB-1 as both a prognostic biomarker and a promising therapeutic target.

molecular biology↗

bioRxiv2025

Targeting SCD in SCD-amplified prostate cancer inhibits growth in bone by modulating cellular stress, mTOR, and DNA damage pathways

The bone microenvironment is abundant in adipocytes and fosters metastatic progression, but the underlying mechanisms are not fully understood. We hypothesize that Stearoyl-Coenzyme A Desaturase (SCD) acts as a tumor-promoting enzyme by modulating cellular stress to support the growth and survival of prostate cancer (PCa) in bone. We observe that SCD-amplified PCa cells are highly sensitive to SCD loss and show reduced PCa spheroid size, diminished mTOR signaling, and increased ER stress. Notably, SCD expression is further increased by adipocytes in SCD-amplified cell lines, and its loss increases DNA damage and activates repair pathways in PCa cells only when exposed to adipocytes. Furthermore, we observe PCa cell lines utilize SCD to regulate adipocyte-induced lipid peroxidation. Aligned with these results, pharmacological SCD inhibition in mice bearing SCD-amplified bone tumors reduces tumor size and reveals histochemical evidence of increased ER stress and DNA damage. Collectively, our data highlight the impact of SCD loss on SCD-amplified tumors and suggest germline characteristics of tumors may dictate their response to redox insult and the possibility of targeting DNA repair pathways in combination with SCD inhibition.

cancer biology↗