Biology subjects

Groves, S.

Publications and source records attributed to Groves, S..

3 recordsLinked to original sources

bioRxiv2025

YAP1 defines an emergent, plastic population of relapsed small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by rapid onset of chemoresistance and poor clinical outcomes. Transcriptional heterogeneity among treatment-naive SCLC tumors underlies four transcriptional subtypes, each with distinct clinical vulnerabilities. Though previously hypothesized to delineate a distinct subtype, expression of YAP1 is largely absent from treatment-naive, pure SCLC. To characterize relapsed SCLC, circulating tumor DNA, circulating tumor cells, and core needle biopsies from SCLC patients and preclinical models following resistance to standard-of-care therapies were analyzed. In contrast to treatment-naive SCLC, these analyses reveal an emergent YAP1-positive cell population that coincides with treatment resistance. These YAP1-positive cells exhibit characteristics of drug tolerant persister cells, including senescence, stemness, and plasticity, as YAP1 positive cells largely abandon features characteristic of SCLC to adopt those of large-cell neuroendocrine carcinoma (LCNEC). As a result of this SCLC-like to LCNEC-like evolution, YAP1-positive cells lack several clinically relevant SCLC surface targets (i.e., DLL3, SEZ6), but are enriched for others (i.e., B7-H3, TROP2). We propose a model where YAP1 expressing cells emerge with SCLC treatment resistance and characterize a tenacious subpopulation capable of diverging from the treatment naive lineage and adopting features to evade therapeutic response.

cancer biology↗

bioRxiv2022

Identifying targetable metabolic dependencies across colorectal cancer progression

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system - comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.

cancer biology↗

bioRxiv2017

Endogenous synthesis of pyrethrins by cannabis

Pyrethrins are a class of natural terpenoid pesticides produced by Tanacetum cinerariifolium, commonly known as chrysanthemum. Here we present evidence that cannabis may be able to produce pyrethrins endogenously. Flower from a cannabis plant grown in a closed hydroponic environment contained 2.48 parts per million pyrethrin I by weight. A comparison of the genetics of T. cinerariifolium and Cannabis demonstrates Cannabis homologues of the genes that contribute to pyrethrins production in T. cinerariifolium. This provides a plausible pathway for the biosynthesis of pyrethrins in cannabis. Although preliminary, these data indicate a potentially significant confounding variable in both cannabis research and regulations on allowable pyrethrins residues in cannabis products.

plant biology↗