Biology subjects

Yip, J.

Publications and source records attributed to Yip, J..

4 recordsLinked to original sources

bioRxiv2026

WNT-driven chromosomal instability as a biomarker for PORCN inhibition

Targeting Porcupine (PORCN), a key regulator of the WNT-signalling pathway, has shown therapeutic potential in multiple cancers. Despite strong target engagement and acceptable safety profiles through human phase I clinical trials, low phase II efficacy has stalled further clinical development. Given that aberrant WNT signalling can drive tumorigenesis by inducing chromosomal instability (CIN), we hypothesised that genomic CIN signatures might serve as a predictive biomarker to help improve response rates. Using a controlled in vitro model and single-cell whole-genome sequencing, we demonstrate that acute WNT-activation directly induces three distinct types of CIN: whole genome duplication, replication stress, and impaired homologous recombination. We translated these observations into a composite CIN signature biomarker that significantly correlated with both genetic dependency and pharmacological inhibition of PORCN across 195 and 24 cell lines, respectively. Through a large-scale meta-analysis of patient-derived and cell line xenografts, we established that this composite CIN signature biomarker quantitatively predicts in vivo PORCN inhibitor sensitivity (R=-0.71, p<0.002). By applying an optimised biomarker threshold, refined through modelling of human patient data, to the The Cancer Genome Atlas dataset, we successfully retrospectively modelled previous trial results and identified gastroesophageal cancers as a high-prevalence (36.6%) indication for future development. We validated this strategy in a mouse clinical trial of gastric and esophageal xenografts, where biomarker-guided stratification achieved an objective response rate of 60% and significantly decreased risk of progression (HR=0.21, p=0.0345). These data establish an actionable, trail-ready framework for further PORCN inhibitor clinical development.

cancer biology↗

bioRxiv2024

Design of highly functional genome editors by modeling the universe of CRISPR-Cas sequences

Gene editing has the potential to solve fundamental challenges in agriculture, biotechnology, and human health. CRISPR-based gene editors derived from microbes, while powerful, often show significant functional tradeoffs when ported into non-native environments, such as human cells. Artificial intelligence (AI) enabled design provides a powerful alternative with potential to bypass evolutionary constraints and generate editors with optimal properties. Here, using large language models (LLMs) trained on biological diversity at scale, we demonstrate the first successful precision editing of the human genome with a programmable gene editor designed with AI. To achieve this goal, we curated a dataset of over one million CRISPR operons through systematic mining of 26 terabases of assembled genomes and meta-genomes. We demonstrate the capacity of our models by generating 4.8x the number of protein clusters across CRISPR-Cas families found in nature and tailoring single-guide RNA sequences for Cas9-like effector proteins. Several of the generated gene editors show comparable or improved activity and specificity relative to SpCas9, the prototypical gene editing effector, while being 400 mutations away in sequence. Finally, we demonstrate an AI-generated gene editor, denoted as OpenCRISPR-1, exhibits compatibility with base editing. We release OpenCRISPR-1 publicly to facilitate broad, ethical usage across research and commercial applications.

synthetic biology↗

bioRxiv2023

Predicting response to cytotoxic chemotherapy

Cytotoxic chemotherapies have been a crucial part of cancer treatment for over 40 years. While their primary target is cancer cells, they can also harm normal cells, resulting in dose-limiting toxicity. Most chemotherapies were approved before the advent of precision biomarkers, as such, many patients experience severe toxic side effects without any benefit. To address this challenge, we have developed three precision biomarkers to predict response to platins, taxanes, and anthracyclines. Based on chromosomal instability (CIN) signatures, these biomarkers can be computed from a single genomic test. For platins and taxanes, we used CIN signatures related to impaired homologous recombination, while for anthracyclines, we discovered a CIN signature representing micronuclei induction which predicts resistance. In a clinical study involving 41 high-grade serous ovarian cancers, patients predicted to be sensitive by these biomarkers showed significantly prolonged progression-free survival. To further validate the effectiveness of the taxane and anthracycline predictors, we conducted a retrospective randomised control study involving 182 ovarian and 219 breast cancer patients. Patients predicted as resistant showed increased risk of time to treatment failure compared to standard of care, hazard ratios of 1.73 (95%CI=0.98-3.07) for taxane in ovarian, 3.67 (95%CI=2.12-6.34) for taxane in breast, and 1.93 (95%CI=1.22-3.04) for doxorubicin in ovarian. We also found that liquid biopsies can be used to make these predictions in up to 30% of ovarian cancer patients. Our findings highlight the clinical value of CIN signatures in predicting treatment response to various chemotherapies across multiple different types of cancer. The ability to quantify multiple CIN signature biomarkers using a single genomic test offers a unified approach to guide treatment decisions for cytotoxic chemotherapies. Ultimately, this has the potential to transform the current one-size-fits-all chemotherapy approach into a more precise and tailored form of medicine.

cancer biology↗

bioRxiv2021

Heterogeneous pdgfrβ+ cells regulate coronary vessel development and revascularization during heart regeneration

Endothelial cells emerge from the atrioventricular canal (AVC) to form nascent coronary blood vessels in the juvenile zebrafish heart. We found that pdgfr{beta} is first expressed in the epicardium around the AVC and later becomes localized mainly in the mural cells. pdgfr{beta} mutant fish display severe defects in mural cell recruitment and coronary vessel development. pdgfr{beta}+ mural cells are heterogeneous and those associated with coronary arteries also express cxcl12b. Mural cells positive for both pdgfr{beta} and cxcl12b transgenic reporters had elevated expression of smooth muscle cell genes. Interestingly, these mural cells were associated with coronary arteries even in the absence of Pdgfr{beta}, although smooth muscle gene expression was downregulated in these cells. We found that pdgfr{beta} expression dynamically changes in the epicardium derived cells, which we found to be a heterogeneous population. mdka was identified as a gene upregulated in subpopulations of pdgfr{beta}+ cells during heart regeneration. However, pdgfr{beta} but not mdka mutants showed defects in heart regeneration. Our results demonstrated that pdgfr{beta}+ cells and Pdgfr{beta} signaling are essential for coronary development and heart regeneration. SUMMARY STATEMENTHeterogeneous pdgfr{beta} positive cells are present in developing and regenerating zebrafish hearts and are required for development of mural cells and their association with the nascent coronary vessels during zebrafish heart development and regeneration.

developmental biology↗