tbuckley/cabot-search huggingface dataset:
Abstract 2491: Conditional generation of mutational profiles in cancer
Authors: Andy Wu, Hannan Wong, Aakansha Narain, Vedant Sandhu, Jason Pitt
Journal: Cancer Research (2025)

Abstract The accumulation of DNA damage on the cancer genome, often summarized as mutational profiles, is influenced by a complex interplay of environmental and cellular mutagenic conditions. Despite cancer genomics having some of the largest biological datasets in existence collected by pan-cancer consortiums, a significant portion of the diverse spectrum of cancer etiologies is still underrepresented and understudied. We leveraged the power of generative artificial intelligence (Gen AI) to develop MutaGen, a conditional variational autoencoder and generative adversarial network hybrid model (CVAE-GAN), to generate realistic mutational profiles conditioned on various clinical and genetic features. Trained on the PCAWG cohort, MutaGen can generate pan-cancer mutational profiles across four mutation types: single base substitutions (SBS96), small insertions and deletions (ID83), structural variations (SV32), and copy number alterations (CN48). MutaGen's cancer-conditioned generations show high similarities to the real PCAWG samples, with median cosine similarities of 0.98, 0.97, 0.92, and 0.96 for SBS96, ID83, SV32, and CN48 respectively. When conditioned on homologous recombination deficiency (HRD) status, MutaGen can generate zero-shot (i.e. cases not seen in training set) HRD lung cancers with high similarity to a real BRCA2-null lung cancer patient in both SBS96 and ID83 (0.93 and 0.78 cosine similarities respectively). The generation is significantly more similar than non-HRD lung cancer or non-lung HRD cancer in the PCAWG training set. Inspection of the generated profiles revealed the generations harbouring both lung cancer-associated and HRD-associated mutational patterns, showing that MutaGen can generate novel and biologically plausible profiles. By providing a versatile tool for generating synthetic mutational data, MutaGen can facilitate the exploration of understudied cancer subtypes and enable the training and benchmarking of predictive models. Citation Format: Andy Wu, Hannan Wong, Aakansha Narain, Vedant Sandhu, Jason Pitt. Conditional generation of mutational profiles in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2491.
Abstract 2621: Mitotic activities of Ewing sarcoma proteins
Authors: Evan Schulz, Mizuki Azuma
Journal: Cancer Research (2025)

Ewing sarcoma (ES) is a pediatric bone tumor in critical need of targeted chemotherapies with fewer side effects. ES’s driving hallmark, the t(11:22) chromosomal translocation, generates two aberrations of the EWS protein: the loss of an EWS allele and expression of EWS/FLI1 fusion protein, denoted as EWS aberrations. Identifying drug targetable EWS aberration-induced changes to tumor biology and drug sensitivity is required to optimize current treatment strategies and develop new targeted therapies. To accomplish this, we established a DLD-1 cell line that lacks the t(11:22) chromosomal translocation and EWS aberrations, while enabling conditional EWS/FLI1 expression with doxycycline (Tet-On system), single-allele EWS knockdown with auxin (auxin-inducible degron system), or a combination of both (EWS/FLI1-EWS KD). This allows us to dissect the contribution of each EWS aberration to phenotypic changes in the cell. Since EWS is a known regulator of tubulin acetylation, we investigated whether tubulin acetylation levels changed under EWS aberration conditions. Both immunocytochemistry and western blotting revealed EWS/FLI1 expressing and EWS/FLI1-EWSKD cells displayed lower acetylated tubulin signal intensity after one and seven days, while EWS knockdown cells displayed higher acetylated tubulin signal intensity. As tubulin acetylation prevents microtubule damage, we probed cells with an antibody that visualizes microtubule damage and repair sites. EWS/FLI1 expressing and EWS/FLI1-EWS KD cells exhibit a higher signal intensity, covering a broader area compared to the control cells. Our data suggests that the combination of EWS/FLI1-EWS KD increases microtubule damage sites by reducing microtubule acetylation. When the EWS/FLI1-EWS KD cells were treated with nocodazole, the rate of cell death increased compared to control nocodazole-treated cells, indicating the cells had been sensitized to microtubule disruption. Currently, we are investigating how EWS aberrations change the regulation of microtubule acetylation and how this mechanism affects sensitivity to microtubule disruptors. Understanding this mechanism could identify new drug targets and treatment strategies in ES to improve drug efficacy and reduce secondary side effects for patients. Citation Format: Evan Schulz, Mizuki Azuma. Mitotic activities of Ewing sarcoma proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2621.
Abstract 1385: Mitochondrial-Nuclear Retrograde Regulator 1 (MNRR1): A novel regulator of apoptosis
Authors: Habiba Elshenawy, Jessica Wu, Neeraja Purandare, Siddhesh Aras
Journal: Cancer Research (2025)

Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1, aka CHCHD2) is a bi-organellar regulator protein localized in the mitochondria and the nucleus. In the mitochondria, MNRR1 regulates oxidative phosphorylation (OxPhos) to generate ATP and inhibits intrinsic apoptosis. Nuclear MNRR1 regulates the transcription of ∼ 5000 genes, including many cancer-related genes. Reasonably, this explains the upregulated MNRR1 expression in different cancers. Triple-negative breast Cancer (TNBC) is associated with an aggressive phenotype. The lack of hormonal receptors and tumor heterogeneity cause resistance to conventional therapies and the inability to develop targeted treatments. Using TNBC as a model system, we aim to identify the mechanism of MNNR1 function as an anti-apoptotic protein. Intrinsic apoptosis involves disruption of equilibrium between pro- and anti-apoptotic proteins. Anti-apoptotic proteins are translocated upon apoptotic stimuli by pro-apoptotic proteins that accumulate on the outer mitochondrial membrane (OMM), causing its permeabilization. This allows the release of cytochrome c from mitochondria to cytosol to activate the caspase pathway. Our findings show that MNRR1 resides in two different forms in the mitochondria based on its Y99 phosphorylation (pY99R1). pY99R1 induces OxPhos, while the non-phosphorylated protein (npR1) interacts preferentially with the anti-apoptotic protein Bcl-xL. Induction of MNRR1 inhibition using knockout cells or chemical inhibitors sensitize cells to an apoptotic stimulus. MNRR1 knockout cells display a pro-apoptotic phenotype as observed by Bax oligomerization. Voltage-dependent anion channel (VDAC) is an OMM protein that interacts with Bcl-xL, preventing the release of cytochrome c to the cytosol. Our study shows that npR1 enhances the VDAC-Bcl-xL interaction complex. This anti-apoptotic function is facilitated by N-terminal 52 amino acids constituting the putative Mitochondrial localization Sequence (MLS) in MNRR1 protein. Collectively, the findings of our study highlight the potential use of MNRR1 as a therapeutic target for novel therapeutics or in combination with existing therapies in TNBC. Citation Format: Habiba Elshenawy, Jessica Wu, Neeraja Purandare, Siddhesh Aras. Mitochondrial-Nuclear Retrograde Regulator 1 (MNRR1): A novel regulator of apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1385.
Abstract 6242: Adaptive therapy in advanced basal cell carcinoma driven by imaging and mathematical modeling
Authors: Jill Gallaher, M A Masud, Zeynep Eroglu, Alexander R. A. Anderson
Journal: Cancer Research (2025)

Abstract Basal cell carcinoma (BCC) accounts for 80% of skin cancers and in most cases is very treatable. However, due to either neglect or aggressive growth, roughly 1-10% of BCCs are considered advanced and infiltrated into surrounding tissue such that it is challenging to clear without causing morbidity. These advanced cancers are treated with a systemic therapy inhibiting the Hedgehog signaling pathway, such as vismodegib, which is mutated in 85% of BCCs. Whilst Hedgehog inhibitors have a median progression-free survival (PFS) of approximately 1 year, they come with significant toxicity that often disrupts standard treatment scheduling, and even for those that can tolerate it, there is the possibility of treatment resistance. Here we show interim results from an ongoing clinical trial (NCT05651828) where we design an adaptive therapy strategy for BCC to increase PFS by controlling growth whilst reducing toxicity and the risk of treatment resistance. We use measurements and photographic images of skin lesions over time integrated with a mathematical model to adapt treatment scheduling (either on or off) in a dynamic patient-specific manner. We develop a burden metric based on the color and texture of a lesion to define its current state. We also define a system of ordinary differential equations comprising sensitive and resistant cells along with compartments to capture the drug’s unique pharmacodynamics to make predictions for future treatments. We fit the model to each patient’s lesion dynamics and predict when to start and stop therapy, iteratively driving treatment decisions in our ongoing clinical trial. We find considerable heterogeneity amongst patients due to the number, size, and morphology of lesions and amongst lesions within a single patient. Drug response and clearance rate of the drug may differ between patients and lesions, so pharmacokinetics and pharmacodynamics parameters need to be carefully calibrated to make good response predictions. Importantly, we define a new strategy for treatment of multiple lesions that are responding differently to treatment within the same patient. We can predict BCC patient growth and response dynamics by fitting a mathematical model to a novel tumor burden metric based on size, color, and texture. Citation Format: Jill Gallaher, Masud M A, Zeynep Eroglu, Alexander R. A. Anderson. Adaptive therapy in advanced basal cell carcinoma driven by imaging and mathematical modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6242.
Abstract 1623: Mechanistic insights into low-frequency ultrasound-induced cancer cell apoptosis
Authors: Aditi Singh, Felix Margadant, Michael Sheetz
Journal: Cancer Research (2025)

Abstract Cancer cells undergo rigidity independent growth due to low expression of mechanosensory cytoskeletal protein known as tropomyosin 2.1, acting as rigidity sensing module. This enables their survival on soft matrices by inciting distinct response to the mechanical cues, in contrast to non-transformed cells. We previously found that treatment of cancer cells with low-frequency ultrasound results in calcium influx through activation of piezo1 channels, microtubule depolymerization through calpain proteases, activation of RhoA-ROCK pathway and increased myosin IIA-mediated actomyosin contractility, ultimately causing cell death in calcium-induced calcium release manner. However, the underlying processes connecting the initiation of apoptosis upon mechanical stimuli remain inadequately understood. Our research focus involves ER-mitochondrial stress pathway comprising of mitochondria-associated ER membranes (MAMs), that might be involved in causing apoptosis in cancer cells exhibiting variations in their mechanoresponse via differential cell killing, while leaving the normal cells unaffected. Recently, we found lowering of mitochondrial membrane potential in cancer cells post-ultrasound treatment. Mitochondrial distribution of normal and cancer cells after ultrasound treatment varied dramatically, leading to increased punctate forms in cancer cells. Inhibition of mitochondrial fission showed significant decrease in apoptosis of cancer cells after ultrasound treatment. We conclude crucial role of mitochondrial fission, ROS and electron transport chain in low-frequency ultrasound-mediated apoptosis in cancer cells along with the cytoskeletal proteins. Tuning of desired parameters involving frequency, pressure and pulse duration could aid in the development of non-invasive cancer therapeutics. Citation Format: Aditi Singh, Felix Margadant, Michael Sheetz. Mechanistic insights into low-frequency ultrasound-induced cancer cell apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1623.
Abstract 1988: Detection of minimal residual disease using cell free plasma DNA to guide maintenance therapy in high grade serous ovarian cancer
Authors: Pamela Soberanis Pina, Stephenie D. Prokopec (co-primary author), Eduardo Gonzalez Ochoa, Derek Wong, Tracy Stockley, Amit Oza, Neesha C. Dhani, Robert C. Grant, Nitthusha Singaravelan, Alexander Fortuna, Bernard Lam, Ilinca Lungu, Madhuran Thiagarajah, Faridah Mbabaali, Sharanjit Singh, Danny Xie, Steven Siman, Judy Quintos, Valerie Bowering, Lisa Wang, Stephanie Lheureux (co-corresponding author), Trevor Pugh (co-corresponding author)
Journal: Cancer Research (2025)

Purpose: Optimal maintenance strategy following re-challenge with platinum-based chemotherapy in patients with relapsed high grade serous ovarian cancer (HGSOC) after PARP inhibitor (PARPi) therapy remains to be established. Use of cell-free DNA (cfDNA) sequencing to detect minimal residual disease (MRD) has emerged as a promising strategy to identify patients at higher risk of relapse who might benefit from more timely, additional treatment. Methods: Nineteen patients with histologically confirmed TP53 mutant HGSOC with platinum sensitive relapse were enrolled into an interventional cfDNA study selecting for patients with confirmed MRD (NCT04510584). Each patient provided a blood sample at the end of standard-of-care platinum treatment (pre or post cycle 6) from which cfDNA was analyzed using targeted sequencing (10,000X coverage) using a 10 gene panel. As a comparator, 30X cell-free whole genome sequencing (cfWGS) was performed for tumour-informed genome-wide mutational sampling benchmarked against 13 platinum-sensitive HGSOC patients and 25 healthy controls. Results: The targeted panel approach detected a somatic TP53 mutation in 1/19 patients above the limit of detection of 1%. In contrast, 30X cfWGS identified evidence of MRD in 8/19 patients (47%) with detection of 319-2,327 known somatic mutations sampled genome-wide (including single-read evidence for 4 somatic TP53 mutations). Genome-wide fragmentomics approaches further identified MRD in 17/19 platinum-resistant patients (89%). Conclusions: cfWGS can be used to examine numerous features capable of identifying patients likely to experience rapid relapse of high grade serous ovarian cancer. Citation Format: Pamela Soberanis Pina, Stephenie D. Prokopec (co-primary author), Eduardo Gonzalez Ochoa, Derek Wong, Tracy Stockley, Amit Oza, Neesha C. Dhani, Robert C. Grant, Nitthusha Singaravelan, Alexander Fortuna, Bernard Lam, Ilinca Lungu, Madhuran Thiagarajah, Faridah Mbabaali, Sharanjit Singh, Danny Xie, Steven Siman, Judy Quintos, Valerie Bowering, Lisa Wang, Stephanie Lheureux (co-corresponding author), Trevor Pugh (co-corresponding author). Detection of minimal residual disease using cell free plasma DNA to guide maintenance therapy in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1988.
Abstract 1283: Targeted genetic profiling of a de novo neuroendocrine patient-derived xenograft (PDX) and organoid model of prostate cancer from patient with African Ancestry
Authors: Diana Rodriguez, Surendra Gulla, Tej Sharma, John Bodkin, Roberto Pili, John E. Tomaszewski, Remi M. Adelaiye-Ogala
Journal: Cancer Research (2025)

Abstract Patient-derived xenograft (PDX) and organoid (PDO) models provide platforms to study prostate cancer (PCa) progression and therapy, especially in underrepresented populations. Here we report the first de novo neuroendocrine prostate cancer (NEPC) from a consented patient of African Ancestry with localized disease and no prior treatment before radical prostatectomy. African American patient had a pTN2 tumor, Gleason7 (4+3) and PSA or 3.6. Acquired tissue was collected for PDX and PDO establishment as well as for downstream molecular characterization. To uncover genetic drivers of aggressive phenotypes, we performed whole exome sequencing on DNA from the primary tumor and the established PDX using the Illumina Exome Kit and Twist Biosciences Exome Panel 2.0, followed by bioinformatic analysis. Computational workflows using Nextflow, including nf-core/sarek, identified somatic single nucleotide polymorphisms (SNPs), mutations (Mutect2, Strelka), and copy number variations (CNVs) (CNVkit, Control-FREEC). Variant annotation with Variant Effect Predictor and SnpEff linked variants to cancer progression. Analysis of the tumor samples revealed CNAs and mutations in genes similar to those seen in previously published NEPC. Protein expression by western blot and IHC identified altered protein expression peculiar to the NEPC phenotype further validating our primary tissue and its derived PDX models to have the NEPC phenotype. Furthermore, novel markers identified provide insight into molecular drivers of this prostate cancer phenotype and may inform targeted therapies for high-risk localized PCa. Citation Format: Diana Rodriguez, Surendra Gulla, Tej Sharma, John Bodkin, Roberto Pili, John E. Tomaszewski, Remi M. Adelaiye-Ogala. Targeted genetic profiling of a de novo neuroendocrine patient-derived xenograft (PDX) and organoid model of prostate cancer from patient with African Ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1283.
Abstract 1624: Stat1 promotes lesion growth and tumor immunity of tuberin-deficient cells in lymphangioleiomyomatosis
Authors: Tasnim Olatoke, Jane Yu
Journal: Cancer Research (2025)

Abstract Lymphangioleiomyomatosis (LAM) is a cystic lung disease that primarily affects women, with an estimated global prevalence of 19 per million women. LAM is caused by the invasion of metastatic smooth muscle-like cells into the lung parenchyma, leading to abnormal cell proliferation and progressive respiratory failure. LAM cells have TSC gene mutations, which occur sporadically or in people with Tuberous Sclerosis Complex. Although it is known that hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) due to TSC2 mutations contributes to aberrant cell growth in LAM lung, tumor origin and invasive mechanism remain unclear. Integrative single-cell omics and validation analyses revealed the activation of a novel uterine-similar HOX/PBX transcriptional network in the LAM lung compared to other lung cells, suggesting that the uterus is one of the origins of LAM cells. Further omics studies indicated that STAT1 and STAT3 interact with PBX1 to increase LAM cell survival. The objective of this study is to delineate mechanisms by which STAT signaling may regulate LAM pathogenesis, with hopes to find potential therapeutic options for LAM and TSC-associated disorders. We hypothesize that STAT1 suppression attenuates LAM patient-derived (TSC2-null) cell viability and tumor growth in LAM. We first confirmed our network prediction analysis by showing that aberrant PBX1 activation upregulates STAT1 in LAM cells and tissues. Our cell viability assays show that STAT1 suppression induced TSC2-null cell apoptosis compared to controls. Similarly, our mouse models show that STAT1 suppression attenuates lung lesion and uterine tumor growth in TSC2-deficient LAM models. We also show that STAT1 activation induced PD-L1 upregulation, indicating that STAT1 helps tumor cells to evade immune surveillance in LAM. Our findings provide proof of concept that STAT1 mediates LAM tumor proliferation through two mechanisms. (1) by promoting lesion growth and (2) by promoting immune evasion via upregulation of PD-L1. STAT1 signaling is critical for LAM cell survival and could be targeted to treat LAM and TSC-associated disorders. Citation Format: Tasnim Olatoke, Jane Yu. Stat1 promotes lesion growth and tumor immunity of tuberin-deficient cells in lymphangioleiomyomatosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1624.