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Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS , and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors. Clonal subpopulations in human tumors are identified from single-cell RNA-seq data.

The deadliest anaplastic thyroid cancer (ATC) often transforms from indolent differentiated thyroid cancer (DTC); however, the complex intratumor transformation process is poorly understood. We investigated an anaplastic transformation model by dissecting both cell lineage and cell fate transitions using single-cell transcriptomic and genetic alteration data from patients with different subtypes of thyroid cancer. The resulting spectrum of ATC transformation included stress-responsive DTC cells, inflammatory ATC cells (iATCs), and mitotic-defective ATC cells and extended all the way to mesenchymal ATC cells (mATCs). Furthermore, our analysis identified 2 important milestones: (a) a diploid stage, in which iATC cells were diploids with inflammatory phenotypes and (b) an aneuploid stage, in which mATCs gained aneuploid genomes and mesenchymal phenotypes, producing excessive amounts of collagen and collagen-interacting receptors. In parallel, cancer-associated fibroblasts showed strong interactions among mesenchymal cell types, macrophages shifted from M1 to M2 states, and T cells reprogrammed from cytotoxic to exhausted states, highlighting new therapeutic opportunities for the treatment of ATC.

Cisplatin is commonly utilized in the treatment of solid tumors. Its mechanism of action is complex and multiple mechanisms of resistance have been described. We sought to determine the impact of cisplatin-generated oxidative stress on head and neck squamous cell carcinoma (HNSCC) proliferation, survival and metabolic activity in order to identify a potential metabolic signature associated with cisplatin response. DNA-bound cisplatin represents a small fraction of total intra-cellular cisplatin but generates a robust oxidative stress response. Neutralization of oxidative stress reverses cisplatin toxicity independent of the mechanism of cell death and TP53 mutational status. Cisplatin-induced oxidative stress triggers rapid shifts in carbon flux in 3 commonly utilized catabolic pathways: glycolysis, pentose phosphate pathway and citric acid cycle. Among these metabolic shifts, decreased flux from pyruvate into lactate is the only metabolic effect consistently observed across multiple HNSCC cell lines of varying genomic backgrounds and may reflect differential cisplatin sensitivity. Oxidative stress is a critical component of cisplatin cytotoxicity in HNSCC and is reflected in acute changes in carbon flux from pyruvate into lactate. This suggests that lactate may contribute to a metabolic signature of acute cisplatin toxicity, and could prove useful in optimizing cisplatin-based treatment regimens in HNSCC.

Hypoglossal neuropathy is the most common lower cranial neuropathy detected as a delayed sequelae of Human Papillomavirus (HPV) -driven oropharyngeal cancer (OPC). Needle electromyography (EMG) is the gold standard for electrodiagnostic testing, but it is invasive and relies on subjective interpretation of the EMG signal. This study explores the potential of non-invasive high-density surface electromyography (HDSEMG) to detect and quantify hypoglossal neuropathy in OPC survivors. In an exploratory study, examine the feasibility of HDSEMG for rapid, non-invasive screening of hypoglossal nerve (CN XII) function and estimate the prevalence of hypoglossal neuropathy before and after oropharyngeal radiotherapy, and associate with patient-reported and clinician-graded functional outcomes. Machine learning performance will be measured through sensitivity, specificity, and F1 score, with a target area under the curve > 0.7 based on literature-reported EMG sensitivity and specificity. This protocol will recruit patients aged ≥ 18 years who receive radiation therapy for OPC at MD Anderson Cancer Center (MDACC) between 2024-2025 and consent to experimental HDSEMG testing. Sanchez Research Lab (The University of Utah, Salt Lake City, UT) will perform data analysis. Clinical data-including electrical impedance measurement (EIM), patient-reported outcomes, dysphagia grading, tongue functions, fibrosis grading, and needle EMG-will be collected from n = 36 patients. Features extracted from HDSEMG will be correlated with other clinical outcomes and used to train a machine learning classifier to quantify the severity of hypoglossal neuropathy.

Background The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. Methods We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002–2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival ( p  < 0.05). Results Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis ( p  = 0.002, p  = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn’t differ significantly from HPV- patients ( p  = 0.72, p  = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p  = 0.03, 76% vs 88.3%; p  = 0.07, and 52.3% vs 74%; p  = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. Conclusions Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

Background Epithelial cell adhesion molecule (EpCAM) is a pleotropic transmembrane glycoprotein comprising an extracellular domain (EpEX), a single transmembrane domain, and an intracellular domain (EpICD). For several types of cancer, high EpCAM expression is associated with tumor progression, metastasis, immune evasion, and overall poor prognosis. A rare but aggressive form of thyroid cancer, anaplastic thyroid cancer (ATC), has a mean survival time of only 3–6 months after diagnosis. Methods The levels of EpEX and EpICD cleavage in clinical patient samples was evaluated by using tissue microarray. Capture enzyme-linked immunosorbent assay (ELISA) was conducted to explore the of shedding EpEX and TNF-α. Western blotting and qRT-PCR was taken to determine the expression of proteins in ATC cell lines. RNA-seq was conducted, and differential gene expression and gene set enrichment analyses were subsequently performed to identify EpCAM knockout–associated molecular alterations and affected biological pathways. The functions of EpCAM or EpEX in ATC were investigated by proliferation, invasion, and stemness analysis. The combined therapy was validated via a tail vein injection method for the metastasis ATC models. Results In this study, we observed that ATC samples typically exhibited a marked loss of membrane EpEX along with increased nuclear and cytoplasm accumulation of EpICD, as compared to non-ATC samples. Furthermore, we found that EpEX induced phosphorylation of EGFR, HGFR and Wnt receptors in ATC cells to promote cell growth, invasion and stemness activity. EpCAM signaling also increases TNF-α expression and induces TNF-α cleavage, and clarify the crosstalk between EpCAM and TNF-α to regulate ERK-EGR1 axis signaling. The inhibition of EpCAM signaling suppressed regulated intramembrane proteolysis (RIP) of EpCAM and shedding of the EpEX and EpICD in ATC cells. Combined treatment of EpAb2-6 and BRAF inhibitor dabrafenib coordinately induced apoptosis, while also inhibiting invasion, stemness and lung metastasis, and prolong survival in an animal model of metastatic ATC. Conclusions This study uncovers the molecular mechanisms underlying promotion of anaplastic thyroid cancer (ATC) tumor progression by EpCAM signaling via the ERK-EGR1-TNF-α axis. Our findings suggest that the EpCAM neutralizing antibody may improve the therapeutic efficacy of BRAF inhibitor, dabrafenib, in ATC.

Although most follicular-derived thyroid cancers are well differentiated and have an overall excellent prognosis following treatment with surgery and radioiodine, management of advanced thyroid cancers, including iodine refractory disease and poorly differentiated/undifferentiated subtypes, is more challenging. Over the past decade, better understanding of the genetic drivers and immune milieu of advanced thyroid cancers has led to significant progress in the management of these patients. Numerous targeted kinase inhibitors are now approved by the U.S Food and Drug administration (FDA) for the treatment of advanced, radioiodine refractory differentiated thyroid cancers (DTC) as well as anaplastic thyroid cancer (ATC). Immunotherapy has also been thoroughly studied and has shown promise in selected cases. In this review, we summarize the progress in the understanding of the genetic landscape and the cellular and molecular basis of radioiodine refractory-DTC and ATC, as well as discuss the current treatment options and future therapeutic avenues.

Genetic susceptibility for xerostomia, a common sequela of radiotherapy and chemoradiotherapy for head and neck cancer, is unknown. Therefore, to identify genetic variants associated with moderate to severe xerostomia, we conducted a GWAS of 359 long-term oropharyngeal cancer (OPC) survivors using 579,956 autosomal SNPs. Patient-reported cancer treatment-related xerostomia was assessed using the MD Anderson Symptom Inventory. Patient response was dichotomized as moderate to severe or none to mild symptoms. In our study, 39.2% of OPC survivors reported moderate to severe xerostomia. Our GWAS identified eight SNPs suggestively associated with higher risk of moderate to severe xerostomia in six genomic regions (2p13.3, rs6546481, Minor Allele (MA) = A, ANTXR1 , P  = 4.3 × 10 –7 ; 5p13.2–p13.1, rs16903936, MA = G, EGFLAM , P  = 5.1 × 10 –6 ; 4q21.1, rs10518156, MA = G, SHROOM3 , P  = 7.1 × 10 –6 ; 19q13.42, rs11882068, MA = G, NLRP9 , P  = 1.7 × 10 –5 ; 12q24.33, rs4760542, MA = G, GLT1D1 , P  = 1.8 × 10 –5 ; and 3q27.3, rs11714564, MA = G, RTP1 , P  = 2.9 × 10 –5 . Seven SNPs were associated with lower risk of moderate to severe xerostomia, of which only one mapped to specific genomic region (15q21.3, rs4776140, MA = G, LOC105370826 , a ncRNA class RNA gene, P  = 1.5 × 10 –5 ). Although our small exploratory study did not reach genome-wide statistical significance, our study provides, for the first time, preliminary evidence of genetic susceptibility to xerostomia. Further studies are needed to elucidate the role of genetic susceptibility to xerostomia.

Objectives/Goals: Conventional magnetic resonance imaging (MRI) methods are unable to visualize bone comparable to computed tomography (CT). Radiation therapy can result in post-treatment complications, such as osteoradionecrosis (ORN). We aim to integrate black bone (BB) MRI into routine follow-up MRI scans as an alternative to CT to monitor the development of ORN. Methods/Study Population: We assess the CT, T2-weighted (T2W), and BB MRI scans of 21 head and neck cancer patients without active ORN. All images are acquired within 4 weeks of each other to minimize anatomical variability. The mandibles are manually segmented on each image, and the MR images are registered to the CT to map the CT contour onto the MR images for comparison. Image segmentation evaluation metrics, including dice similarity coefficient (DSC), mean distance to agreement (MDA), and Hausdorff distance (HD), assess for spatial differences between each MRI sequence, using CT as reference standard. DSC measures contour volume, while MDA and HD assess the differences in contour boundaries, with HD sensitive to outliers. We employ a Wilcoxon signed-rank test using a significance value of p≤0.05 to assess for statistical significance. Results/Anticipated Results: Using metrics widely accepted in biomedical research, we assess the performance of BB to visualize mandible against its conventional T2W MRI counterpart when compared to CT. Black bone has a significantly different DSC (median=0.878, IQR=0.0397) than T2W (median=0.806, IQR=0.0876; p<0.0001), indicating high volumetric overlap between contours on BB and CT. Black bone has a significantly different MDA (median=0.0731mm, IQR=0.0227mm) than T2W (median=0.119mm, IQR=0.0697; p<0.0001), indicating high agreement between contour boundaries on BB and CT. Black bone has a significantly different HD (median=0.649mm, IQR=0.211mm) than T2W (median=1.80, IQR=0.933; p<0.0001), indicating a submillimeter difference between contour boundaries, including outliers, on BB and CT. Discussion/Significance of Impact: Our results exhibit BB as a promising non-ionizing alternative to CT for bony visualization compared to conventional MRI. BB has potential to detect early anatomical changes in bone, providing a standardized assessment of ORN. This can improve our dose–response understanding of post-treatment toxicities, refining radiation treatment planning.