Biology subjects

Cosford, N.

Publications and source records attributed to Cosford, N..

3 recordsLinked to original sources

bioRxiv2025

Leveraging autophagy and pyrimidine metabolism to target pancreatic cancer

Autophagy inhibitors are promising compounds to treat pancreatic ductal adenocarcinoma (PDA) but their efficacy in patients is unclear, highlighting a need to understand mechanisms of resistance. We used a novel approach to uncover metabolic adaptations that bypass autophagy inhibition. Utilizing PDA cells with acquired resistance to different autophagy inhibitors, we found that severe autophagy depletion induces metabolic rewiring to sustain TCA intermediates and nucleotides for biosynthesis. Long-term autophagy inhibition results in altered pyruvate metabolism likely regulated by lower pyrimidine pools. Cells adapting to loss of autophagy preferentially salvage pyrimidines to replenish these pools instead of synthesizing them de novo. Exploiting this metabolic vulnerability, we found that acquired resistance to autophagy inhibition promotes increased salvage and therefore sensitivity to pyrimidine analogues, including gemcitabine and trifluridine/tipiracil leading to combinatory effects with autophagy inhibitors and pyrimidine analogs. These studies provide mechanistic insight defining how autophagy inhibition can be leveraged to treat pancreatic cancer.

cancer biology↗

bioRxiv2025

17β-estradiol status alters NMDAR function and antipsychotic-like activity in female rats

Low 17{beta}-estradiol (E2) in females of reproductive age, and marked E2 decline with menopause, contributes to heightened symptom severity in schizophrenia (i.e. cognitive dysfunction) and diminished response to antipsychotic medications. However, the underlying mechanisms are unknown. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to the pathophysiology of schizophrenia, yet impact of E2 depletion on NMDAR function is not well characterized. Quantitative electroencephalography (qEEG), specifically gamma power, is a well-established functional readout of cortical activity that is elevated in patients with schizophrenia and is sensitive to alterations in NMDAR function. Using qEEG and touchscreen cognitive assessments, present studies investigated the effects of E2 on NMDAR function by administering MK-801 (NMDAR antagonist) to ovariectomized rats with or without E2 implants (Ovx+E and Ovx, respectively). Ovx rats were more sensitive to MK-801-induced elevations in gamma power and attentional impairments compared to Ovx+E rats. Further investigation revealed these effects were mediated by reduced synaptic GluN2A expression. Consistent with clinical reports, olanzapine (second-generation antipsychotic) was less effective in mitigating MK-801-induced elevations in gamma power in Ovx rats. Lastly, we examined antipsychotic-like activity of a Group II metabotropic glutamate receptor (mGlu2/3) positive allosteric modulator (PAM), SBI-0646535, as a novel therapeutic in E2-deprived conditions. SBI-0646535 reversed MK-801-induced elevations in gamma power equally regardless of E2 status. Collectively, these studies established a relationship between E2 deprivation and NMDAR function that is in part GluN2A-dependent, supporting the notion that E2 deprivation increases susceptibility to NMDAR hypofunction. This highlights the need to examine age/hormone-specific factors when considering antipsychotic response and designing novel pharmacotherapies.

animal behavior and cognition↗

bioRxiv2021

The autophagy initiating kinase ULK1 is required for pancreatic cancer cell growth and survival

Amongst cancer subtypes, pancreatic ductal adenocarcinoma (PDA) has been demonstrated to be most sensitive to autophagy inhibition, which may be due to unique metabolic rewiring in these cells. The serine/threonine kinase ULK1 forms the catalytic center of a complex mediating the first biochemical step of autophagy. ULK1 directly recieves signals from mTORC1 and AMPK to trigger autophagy under stress and nutrient poor conditions. Studies in genetic engineered mouse models of cancer have revealed that deletion of core downstream autophagy genes (ATG5, ATG7) at the time of tumor iniation leads to a profound block in tumor progression leading to the development of autophagy inhibitors as cancer therapeutics. However, most preclinical studies and all clinical studies have relied on non-specific lysomotropic agents such as chloroquine and its derivatives, whose toxicity and off-target issues preclude further clinical development and which do not represent the impact of solely biochemically disrupting the autophagy pathway. Furthermore, druggable targets in the core autophagy pathway are quite limited, with ULK1 and ULK2 representing the only protein kinases in the pathway. Here we explore the genetic requirement for ULK1 and ULK2 in human PDA cancer cell lines and xenografts, and take advantage of new small molecule ULK1 inhibitors to demonstrate that ULK inhibition can overcome autophagy induction triggered by PDA therapeutics including chemotherapy and MEK inhibition. Finally we show that ULK inhibitors increase MHC Class I in PDA cells, suggestion a potential therapeutic avenue for such agents in combination with checkpoint immunotherapy.

cancer biology↗