Biology subjects

Corless, C. L.

Publications and source records attributed to Corless, C. L..

3 recordsLinked to original sources

bioRxiv2025

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

cancer biology↗

bioRxiv2025

Clinical and molecular features of primary gliosarcoma with digital spatial whole-transcriptome analysis of glial and mesenchymal components

Gliosarcoma is a rare subtype of IDH-wildtype glioblastoma defined by mixed malignant glial and high-grade sarcomatous histological elements. Gliosarcoma is clinically managed similarly to glioblastoma and has a poor clinical outcome. The sarcoma-like regions of gliosarcoma are thought to represent extreme mesenchymal metaplasia of neoplastic glial cells. Factors contributing to this phenomenon are not completely understood. Here we report a single-institution series of 37 gliosarcomas including next-generation sequencing data on 25 cases and digital spatial whole-transcriptome analysis on 4 cases to characterize differential gene expression between glial and mesenchymal components. Gliosarcoma demographic and genetic features were compared to a cohort of 75 primary adult hemispheric IDH-wildtype non-sarcomatous glioblastomas. Patient age, tumor location, sex, and overall survival in gliosarcoma were similar to glioblastoma. Gliosarcomas showed a significantly lower rate of EGFR amplification and a higher rate of NF1 mutation compared to glioblastomas in next-generation sequencing analysis. Digital spatial whole-transcriptome analysis showed a distinct transcriptomic profile in sarcomatous regions with over-expression of genes involved in extracellular matrix development and remodeling. Selected differentially expressed transcripts were examined further by immunohistochemistry. The glial elements of gliosarcomas showed higher immunoreactivity for Chitinase-3-like protein 1 (CHI3L1) than glioblastomas, but low to absent expression within the sarcomatous elements. Lymphoid Enhancer-Binding Factor 1 (LEF1) immunoreactivity was identified within sarcomatous regions of gliosarcoma without detectable nuclear {beta}-catenin, suggesting a role for {beta}-catenin independent wingless (WNT) effector signaling in sarcomatous transformation. This study adds to the growing literature demonstrating differences in the genetic underpinning of gliosarcoma and glioblastoma, establishes feasibility of spatial transcriptomic approaches in gliosarcoma, and validates digital spatial profiling-based results as a discovery platform to identify pathways and immunohistochemical markers for further study.

pathology↗

bioRxiv2023

Longitudinal and multimodal auditing of tumor adaptation to CDK4/6 inhibitors in HR+ metastatic breast cancers

CDK4/6 inhibitors (CDK4/6i) have transformed the treatment of hormone receptor-positive (HR+), HER2-negative (HR+) breast cancers as they are effective across all clinicopathological, age, and ethnicity subgroups for metastatic HR+ breast cancer. In metastatic ER+ breast cancer, CDK4/6i lead to strong and consistent improvement in survival across different lines of therapy. To improve understanding of how metastatic HR+ breast cancers become refractory to CDK4/6i, we have created a multimodal and longitudinal tumor atlas to investigate therapeutic adaptations in malignant cells and in the tumor immune microenvironment. This atlas is part of the NCI Cancer Moonshot Human Tumor Atlas Network and includes seven pairs of pre- and on-progression biopsies from five metastatic HR+ breast cancer patients treated with CDK4/6i. Biopsies were profiled with bulk genomics, transcriptomics, and proteomics as well as single-cell ATAC-seq and multiplex tissue imaging for spatial, single-cell resolution. These molecular datasets were then linked with detailed clinical metadata to create an atlas for understanding tumor adaptations during therapy. Analysis of our atlas datasets suggests a diverse set of tumor adaptations to CDK4/6i therapy. Malignant cells may adapt to therapy via mTORC1 activation, cell cycle bypass, and increased replication stress. The tumor immune microenvironment displayed evidence of both immune activation and immune suppression during therapy. Together, our metastatic ER+ breast cancer atlas represents a rich multimodal resource to better understand HR+ breast cancer tumor therapeutic adaptations to CDK4/6i therapy.

cancer biology↗