Browsing by Author "Khaliq, Ateeq M."

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    High-dimensional deconstruction of pancreatic cancer identifies tumor microenvironmental and developmental stemness features that predict survival
    (Springer Nature, 2023-10-19) Storrs, Erik P.; Chati, Prathamesh; Usmani, Abul; Sloan, Ian; Krasnick, Bradley A.; Babbra, Ramandeep; Harris, Peter K.; Sachs, Chloe M.; Qaium, Faridi; Chatterjee, Deyali; Wetzel, Chris; Goedegebuure, Peter; Hollander, Thomas; Anthony, Hephzibah; Ponce, Jennifer; Khaliq, Ateeq M.; Badiyan, Shahed; Kim, Hyun; Denardo, David G.; Lang, Gabriel D.; Cosgrove, Natalie D.; Kushnir, Vladimir M.; Early, Dayna S.; Masood, Ashiq; Lim, Kian-Huat; Hawkins, William G.; Ding, Li; Fields, Ryan C.; Das, Koushik K.; Chaudhuri, Aadel A.; Medicine, School of Medicine
    Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n = 25). We then combined these samples with surgical resection (n = 6) and publicly available samples to increase statistical power (n = 80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness, and a customized version of the Ecotyper tool was used to identify communities of co-occurring cell states in bulk RNA-seq samples (n = 268). We discovered a tumor microenvironmental community comprised of aggressive basal-like malignant cells, tumor-promoting SPP1+ macrophages, and myofibroblastic cancer-associated fibroblasts associated with especially poor prognosis. We also found a developmental stemness continuum with implications for survival that is present in both malignant cells and cancer-associated fibroblasts (CAFs). We further demonstrated that high-dimensional analyses predictive of survival are feasible using standard-of-care, time-of-diagnosis EUS-FNB specimens. In summary, we identified tumor microenvironmental and developmental stemness characteristics from a high-dimensional gene expression analysis of PDAC using human tissue specimens, including time-of-diagnosis EUS-FNB samples. These reveal new connections between tumor microenvironmental composition, CAF and malignant cell stemness, and patient survival that could lead to better upfront risk stratification and more personalized upfront clinical decision-making.
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    Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine
    (Elsevier, 2025) Nagaraju, Ganji Purnachandra; Saddala, Madhu Sudhana; Foote, Jeremy B.; Khaliq, Ateeq M.; Masood, Ashiq; Golivi, Yuvasri; Bandi, Dhana Sekhar Reddy; Sarvesh, Sujith; Reddy, Sudhir Putty; Switchenko, Jeffrey; Carstens, Julienne L.; Akce, Mehmet; Herting, Cameron; Alese, Olatunji B.; Yoon, Karina J.; Manne, Upender; Bhasin, Manoj K.; Lesinski, Gregory B.; Sukhatme, Vikas P.; El-Rayes, Bassel F.; Medicine, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4+ and CD8+ T cells and reduces CD4+ and CD8+ regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial.
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    Refining colorectal cancer classification and clinical stratification through a single-cell atlas
    (Springer, 2022-05-11) Khaliq, Ateeq M.; Erdogan, Cihat; Kurt, Zeyneb; Turgut, Sultan Sevgi; Grunvald, Miles W.; Rand, Tim; Khare, Sonal; Borgia, Jeffrey A.; Hayden, Dana M.; Pappas, Sam G.; Govekar, Henry R.; Kam, Audrey E.; Reiser, Jochen; Turaga, Kiran; Radovich, Milan; Zang, Yong; Qiu, Yingjie; Liu, Yunlong; Fishel, Melissa L.; Turk, Anita; Gupta, Vineet; Al-Sabti, Ram; Subramanian, Janakiraman; Kuzel, Timothy M.; Sadanandam, Anguraj; Waldron, Levi; Hussain, Arif; Saleem, Mohammad; El-Rayes, Bassel; Salahudeen, Ameen A.; Masood, Ashiq; Medicine, School of Medicine
    Background Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. Results Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. Conclusions Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.