tbuckley/cabot-search huggingface dataset:
Abstract LB395: NetraAI-driven discovery of novel biomarkers in MSI-high colon cancer for precision immunotherapy
Authors: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci
Journal: Cancer Research (2024)

Abstract By leveraging NetraAI, a novel machine learning (ML) approach, we identify potential biomarkers in microsatellite instability-high (MSI-H) colon cancer. MSI, marked by DNA mismatch repair (MMR) defects characterizes 5-20% of colorectal cancers (CRCs). MSI-H tumors harbor higher mutational burdens, produce neoantigens, and enhance immune recognition and responsiveness to immunotherapy. The innovative Sub-Insight Learning approach of NetraAI, allows us to overcome challenges associated with smaller data sets not reflecting the totality of the disease they represent. This approach utilizes a set of validated mathematical methods to identify sub-insights about patients even from small data sets. This allows the system to decompose the data sets into high and low confidence patient subpopulations, enhancing predictive model accuracy and reducing overfitting. Further, the system explains what variables are driving the etiology defining the subpopulations of patients. Utilizing a small data set consisting of 141 RNA expression profiles of CRC samples (E-GEOD-41258) with MSI-H and MSI-low colon cancer, we were able to derive several unique insights into patients’ molecular profiles. NetraAI analysis identified several unique variables, including CATSPERB, FUT8, PLLP, DUSP4, and MLPH that may play significant roles in MSI-H colon cancer pathology. These markers hold potential for personalizing clinical trials as well as potential therapeutic targets. Furthermore, protein-protein interaction (PPI) networks revealed co-expression and co-localizations that exist amongst these genes, suggesting a complex interplay among these genes, particularly in the context of spermatogenesis. The application of NetraAI and its Sub-Insight Learning paradigm has revealed novel insights into the molecular profile of MSI-H colon cancer. These findings pave the way for more targeted and effective precision immunotherapy strategies, demonstrating the power of AI in advancing the understanding and treatment of complex cancers. Citation Format: Bessi Qorri, Mike J. Tsay, Paul Leonchyk, Larry Alphs, Luca Pani, Joseph Geraci. NetraAI-driven discovery of novel biomarkers in MSI-high colon cancer for precision immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB395.
Abstract LB410: Contrasting roles of different mismatch repair proteins in basal like breast cancer
Authors: Tanzia Islam Tithi, Jiao Mo, Weizhou Zhang
Journal: Cancer Research (2024)

Abstract The mismatch repair (MMR) pathway is known as a tumor suppressive pathway and genes involved in MMR are commonly mutated in hereditary colorectal or other cancer types. However, the function of MMR genes/proteins in breast cancer progression and metastasis are largely unknown. We found that MSH2, but not MLH1, is highly enriched in basal-like breast cancer (BLBC) and that its protein expression is inversely correlated with overall survival time (OS). MSH2 expression is frequently elevated due to genomic amplification or gain-of-expression in BLBC, which results in increased MSH2 protein to pair with MSH6 (collectively referred to as MutSα). Genetic deletion of MSH2 or MLH1 results in a contrasting phenotype in metastasis, with MSH2-deletion leading to reduced metastasis and MLH1-deletion to enhanced liver or lung metastasis. Mechanistically, MSH2-deletion induces the expression of a panel of chemokines in BLBC via epigenetic and/or transcriptional regulation, which leads to an immune reactive tumor microenvironment (TME) and elevated immune cell infiltrations. MLH1 is not correlated with chemokine expression and/or immune cell infiltration in BLBC, but its deletion results in strong accumulation of neutrophils that are known for metastasis promotion. Our study supports the differential functions of MSH2 and MLH1 in BLBC progression and metastasis, which challenges the paradigm of the MMR pathway as a universal tumor suppressive mechanism. Citation Format: Tanzia Islam Tithi, Jiao Mo, Weizhou Zhang. Contrasting roles of different mismatch repair proteins in basal like breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB410.
Abstract LB225: Regulation of breast cancer stem cell identity by PLK1 and FOXC2
Authors: Joanna Joyce Maddela, Maria Castaneda, Petra den Hollander, Nick Kuburich, Sendurai Mani
Journal: Cancer Research (2024)

Abstract One of the main drivers for the drastic reduction in survival rates caused by metastatic breast cancer is attributed to Epithelial-to-Mesenchymal Transition (EMT). During embryonic development and wound healing, EMT plays a vital role and during cancer pathogenesis, cancer cells reactivate this program to gain plasticity, migration, and invasion promoting metastasis. In addition, EMT also plays a crucial role in generating a subpopulation of highly resilient tumor cells known as cancer stem cells (CSCs). Moreover, following conventional treatment, residual tumor cells that remain after treatment tend to exhibit CSC properties. EMT-induced cancer stem cells exhibit heightened plasticity and stemness, significantly fueling the metastatic spread of cancer and enhancing the endurance and adaptability throughout the process of metastasis. Thus, understanding the molecular intricacies governing stem cell properties holds immense potential for developing targeted therapies to target metastasis and the development of resistance to treatments. To further elucidate EMT-induced cancer stem cell generation, our lab has demonstrated that the Polo-like kinase 1 (PLK1), an important G2/M regulator, plays an important role in the generation of CSCs through Forkhead box protein C2 (FOXC2). Most importantly, we have shown that the FOXC2 transcription factor, known to be crucial in embryonic development, now has emerging roles in metastatic cancer progression. FOXC2 is positioned at the center of the complex network of signal transduction pathways and functions downstream of most EMT-inducing transcription factors. FOXC2 is necessary for the acquisition and maintenance of stem cell property. In addition, we found that phosphorylation of FOXC2 by PLK1 stabilizes, and inhibition of PLK1 causes a decrease in FOXC2 and stemness in cancer cells. This led us to hypothesize that EMT-induced CSC generation is driven by the PLK1-FOXC2 axis. By expressing phosphomimetic and non-phosphorylatable FOXC2 mutants in breast cancer cell lines, we show that PLK1 phosphorylation is necessary for gaining stemness and an increase in symmetric self-renewal type of stem cell division. Evidence will be presented as to how we are targeting the PLK1-FOXC2 axis to make tumors sensitive to standard-of-care treatments. Citation Format: Joanna Joyce Maddela, Maria Castaneda, Petra den Hollander, Nick Kuburich, Sendurai Mani. Regulation of breast cancer stem cell identity by PLK1 and FOXC2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB225.
Abstract LB186: Rapid photoinhibition of the autophagy pathway
Authors: Payel Mondal, Amanda Cyril, Christina Towers
Journal: Cancer Research (2024)

Abstract Autophagy is a highly regulated and conserved cellular recycling process that is activated under stress conditions. Although cancer cells are known to rely on autophagy for survival, recent studies indicate that when the nutrient recycling process is blocked, a few rare cancer cells still can circumvent autophagy inhibition and maintain their aggressive growth rate. To understand the autophagy inhibition adaptation mechanism, we have developed a novel optogenetic autophagy inhibition tool (ASAP) that can rapidly and reversibly block the autophagy pathway in response to blue light. Our preliminary data shows ASAP releases a mutant autophagy inhibitory protein from the plasma membrane within 5 minutes of blue light exposure, blocks autophagosome-lysosome fusion, and induces LC3-II protein accumulation. In comparison, bafilomycin, a known autophagosome-lysosome fusion inhibitor, takes 4-hours to reproduce similar inhibitory effects as ASAP. Additionally, unlike bafilomycin, ASAP-induced autophagy inhibition is reversible within 2-6 hours. As light-induced autophagy inhibition has not been previously tested, our system brings a novelty to the conventional genetic and pharmacological approaches of autophagy inhibition. We will utilize the novel ASAP tool to understand the rapid changes in cellular proteomics and signaling events that dictate autophagy inhibition adaptation in cancer cells. We will perform tandem mass tag (TMT) based total proteomics and phospho-proteomics screen to visualize the temporal kinetics of protein turnover rates and changes in cell-signaling pathways following rapid autophagy inhibition. Additionally, our optogenetic tool will be applied in vivo in C. elegans to rapidly block autophagy and answer key questions of the spatial and temporal roles of autophagy in aging. Citation Format: Payel Mondal, Amanda Cyril, Christina Towers. Rapid photoinhibition of the autophagy pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB186.
Magnetic Resonance Imaging in Prostate Cancer Screening
Authors: Tamás Fazekas, Sung Ryul Shim, Giuseppe Basile, Michael Baboudjian, Tamás Kói, Mikolaj Przydacz, Mohammad Abufaraj, Guillaume Ploussard, Veeru Kasivisvanathan, Juan Gómez Rivas, Giorgio Gandaglia, Tibor Szarvas, Ivo G. Schoots, Roderick C. N. van den Bergh, Michael S. Leapman, Péter Nyirády, Shahrokh F. Shariat, Pawel Rajwa
Journal: JAMA Oncology (2024)

Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway.
Abstract LB208: An intricate connection between canonical Wnt and MAPK/ERK signaling drives the partial hybrid EMT state involving FOXC2/p63 activation leading to cancer stemness and metastasis
Authors: Huizhi Liang, Outhiriaradjou Benard, Zuen Ren, Kimita Suyama, Jingli Wang, Anthony Griffen, Hao Wang, Lindsay LeFave, Larry Norton, Rachel B. Hazan
Journal: Cancer Research (2024)

Abstract The epithelial to mesenchymal transition (EMT) is a dynamic process underlying metastasis. Here we show that TCF1, a TCF7 gene product, promotes a hybrid epithelial/mesenchymal (E/M) phenotype in basal breast cancer cells that was enriched in stemness and metastasis as compared to cells residing in the M-like state. E/M cells (CD104highCD44high) were enriched in canonical Wnt signaling, thereby upregulating FOXC2 which was turn able of converting M into E/M cells. Consistent with the E/M state, FOXC2 upregulated TA and ΔNp63 isoforms which control epithelial differentiation and Wnt signaling via β4 integrin/CD104 and Frizzled 7 upregulation respectively. Importantly, Wnt3a was able of stimulating ERK phosphorylation in E/M cells leading to FOXC2 and p63 upregulation thereby preventing E/M to M differentiation. These findings were further corroborated by ATAC-sequencing pointing predominantly to FOXC2 as a master regulator of the E/M state that was suppressed by ERK inhibition. Together, these results demonstrate that TCF7 stimulates Wnt3a/ERK activation which in turn activates the FOXC2/p63 axis, thereby promoting the hybrid EMT state underlying stemness and metastasis. Citation Format: Huizhi Liang, Outhiriaradjou Benard, Zuen Ren, Kimita Suyama, Jingli Wang, Anthony Griffen, Hao Wang, Lindsay LeFave, Larry Norton, Rachel B. Hazan. An intricate connection between canonical Wnt and MAPK/ERK signaling drives the partial hybrid EMT state involving FOXC2/p63 activation leading to cancer stemness and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB208.
Abstract LB386: Weakly-supervised prediction of tumor infiltrating lymphocytes per high power field from colorectal cancer histopathology slides using regression transformers
Authors: Omar S. El Nahhas, Joseph D. Bonner, Joel K. Greenson, Daniel B. Schmolze, Lawrence Shaktah, Jonathan Salazar, Lorena Reynaga, Sidney Lindsey, Jenny Lu, Victor Moreno, Stephanie L. Schmit, Ya-Yu Tsai, Stanley R. Hamilton, Gad Rennert, Jakob N. Kather, Stephen B. Gruber
Journal: Cancer Research (2024)

Abstract Tumor infiltrating lymphocytes (TILs)-based biomarkers have emerged as a robust method for predicting treatment efficacy and outcome in colorectal cancer (CRC). However, the quantification of TILs remains a strenuous task for pathologists and is susceptible to inter-pathologist variations. Deep learning (DL) can predict cancer biomarkers directly from routine hematoxylin and eosin (H&amp;E) pathology slides, enabling the automated and consistent quantification of TILs for clinical decision-making. Our study focuses on the prediction of TILs per high-power field (HPF) on two large cohorts of CRC patients. We developed a weakly-supervised, transformer-based deep regression model to predict TILs per HPF from routine H&amp;E-stained histology slides. We trained the model using 5-fold cross-validation on a large cohort of CRC patients (n=1,738), and validated its performance on an external cohort of CRC patients (n=223). The model was evaluated using the Pearson’s correlation coefficient r. Moreover, pathologist-determined TILs per HPF was categorized into low (&amp;lt;2) and high (≥2), enabling evaluation via the area under the receiver operating characteristic curve (AUROC). Our model achieved a significant correlation coefficient of 0.60 (p&amp;lt;0.0001) for the predicted TILs per HPF in the holdout test sets of the internal cohort, and a significant correlation coefficient of 0.57 (p&amp;lt;0.0001) on the external validation cohort. Using the thresholds for low and high TILs per HPF, we found that the model accurately predicted the presence of high TILs per HPF in both the internal and external test cohorts, yielding AUROCs of 0.76 and 0.81, respectively. These findings underscore the efficacy of our deep learning model in predicting TILs per HPF from routine pathology slides. This approach holds promise for cost-effective, efficient and uniform quantification of TILs per HPF in CRC, potentially across various cancer types. Citation Format: Omar S. El Nahhas, Joseph D. Bonner, Joel K. Greenson, Daniel B. Schmolze, Lawrence Shaktah, Jonathan Salazar, Lorena Reynaga, Sidney Lindsey, Jenny Lu, Victor Moreno, Stephanie L. Schmit, Ya-Yu Tsai, Stanley R. Hamilton, Gad Rennert, Jakob N. Kather, Stephen B. Gruber. Weakly-supervised prediction of tumor infiltrating lymphocytes per high power field from colorectal cancer histopathology slides using regression transformers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB386.
Abstract LB010: Identification of malignant lung indeterminate pulmonary nodules with Plasma WGS using exon read depth of short DNA fragments
Authors: Shun H. Yip, Neeti Swarup, Jason C. Hyun, Jordan C. Cheng, Raghuraman Ramamurthy, Edmund Wong, Irene Choi, Akanksha Arora, Denise Aberle, David TW Wong, Cheuk Y. Tang
Journal: Cancer Research (2024)

Abstract Background: Plasma WGS for non-invasive cancer detection has been an active area of research, where fragmentomics studies have been gaining attention for its promising results. Previous studies showed that the quantity of short and long fragments could be used for the prognosis of malignant tumor. In this study, the efficacy of short fragment read depth on the reference genome for malignant nodule detection was evaluated. Methods: Plasma samples from 40 patients with Indeterminate Pulmonary Nodules (IPN) (20 with Benign nodule, 20 Malignant) were collected for WGS. Low quality samples were filtered, and 31 patients (15 Benign, 16 Cancer) remained. Short fragments in each sample were extracted (30-99 bp) and exon read depth for each sample was obtained through human reference genome alignment. A proprietary data analytic machine learning pipeline using XGBoost was trained and tested using 10 fold cross validation. Results: XGBoost model testing accuracy was 96.77% in differentiating Benign and Cancer samples using read depth information from only 3 exons. GPR35’s ENSE00003591008.1, ZNF594-DT’s ENSE00002678218.2 and IGHGP’s ENSE00001819760.2 were the 3 exons used in the model. Hierarchical clustering using top features with differential read depth (p&amp;lt;0.001) was able to perfectly cluster the samples into the Benign group and the Malignant group. Conclusion: Read depth information of exon by short fragments from WGS plasma was able to differentiate patients with Lung benign nodules from patients with malignant nodules. This analysis demonstrates promises of developing diagnosis tools using exon read depths from plasma samples. Citation Format: Shun H. Yip, Neeti Swarup, Jason C. Hyun, Jordan C. Cheng, Raghuraman Ramamurthy, Edmund Wong, Irene Choi, Akanksha Arora, Denise Aberle, David TW Wong, Cheuk Y. Tang. Identification of malignant lung indeterminate pulmonary nodules with Plasma WGS using exon read depth of short DNA fragments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB010.
Abstract LB296: Human CYP1B1 enhances cancer progression through induction of Sp1 via DNMT-mediated epigenetic regulation of miR-375
Authors: Young-Jin Chun, Yeo-Jung Kwon, Tae-Uk Kwon
Journal: Cancer Research (2024)

Abstract Human cytochrome P450 1B1 (CYP1B1) is a major catalytic enzyme for metabolism of 17β-estradiol (E2) to catechol estrogens, mainly carcinogenic metabolite 4-hydroxyestradiol (4-OHE2). To identify the unknown molecular mechanism for cancer progression induced by CYP1B1, we studied the role of CYP1B1 in human tumor cells, MCF-7, MDA-MB-231, and HeLa cells. Suppression of CYP1B1 by shRNA significantly reduced cancer cell viability and invasion. Clinical data from cancer patients showed that high level of CYP1B1 expression resulted in relatively lower survival rate. Interestingly, overexpression of CYP1B1 markedly activated Wnt/β-catenin signaling and EMT process, and suppression of specificity protein 1 (Sp1) by siRNA, an well-known transcription factor, demolished the promoting effects of CYP1B1 on cancer progression. To investigate the correlation between CYP1B1 and Sp1, we analyzed the clinical data from breast and cervical cancer patients and the results showed the positive correlation between two genes. Furthermore, TMS (tetramethoxystilbene), a specific CYP1B1 inhibitor, diminished the induction of Sp1 by CYP1B1, and 4-OHE2 exceedingly promoted the expression level of Sp1. Surprisingly, miR-375, known as an oncogenic microRNA, substantially decreased by 4-OHE2 and CYP1B1 overexpression in CYP1B1-transgenic (TG) mice. Methylation specific assay revealed that CYP1B1 suppressed miR-375 expression through induction of hyper-methylation on pre-miR-375. In addition, epigenetic regulation of miR-375 by CYP1B1 was executed via induction of DNA methyltransferases (DNMTs), DNMT1, 3a, and 3b. Enhanced expression level of Sp1 by 4-OHE2 was significantly deteriorated by 5-aza-dC, a DNMT inhibitor. Taken together, our data suggest that CYP1B1 enhances cancer progression through induction of cancer cell proliferation and invasion via DNMT-mediated epigenetic regulation of miR-375 and further promotion of Sp1 expression. Citation Format: Young-Jin Chun, Yeo-Jung Kwon, Tae-Uk Kwon. Human CYP1B1 enhances cancer progression through induction of Sp1 via DNMT-mediated epigenetic regulation of miR-375 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB296.
Abstract LB073: Adoptive transfer of one CD4TCR and one CD8TCR targeting autochthonous neoantigens are essential and sufficient for eradication of naturally heterogeneous solid tumors
Authors: Steven Wolf, Vasiliki Anastasopoulou, Kimberley Drousch, Markus Diehl, Boris Engels, Poh Yin Yew, Kazuma Kiyotani, Yusuke Nakamura, Karin Schreiber, Hans Schreiber, Matthias Leisegang
Journal: Cancer Research (2024)

Abstract Despite advances in checkpoint blockade therapy or adoptive transfer of tumor-infiltrating lymphocytes (TILs), achieving cure remains challenging, but success of immunotherapy seems to depend on recognition of tumor-specific antigens (neoantigens). We aimed to determine how many neoantigens need to be recognized by how many different TCRs for eradication of solid tumors. Unmanipulated, naturally expressed (autochthonous) neoantigens were targeted with adoptively transferred TCR-engineered autologous T cells (TCR-therapy). Investigated were effects of TCR-engineered CD8+ T cells, TCR-engineered CD4+ T cells or a combination of both. The targeted tumors were established for at least three weeks and derived from primary autochthonous cancer cell cultures, resembling natural solid tumors and their heterogeneity as found in humans. CD8TCR-therapy was only effective against homogenous tumors and relapse was common in heterogeneous tumors, even when targeting multiple different autochthonous neoantigens. By contrast, a combination of CD8TCR-therapy with CD4TCR-therapy, each targeting an independent neoantigen, eradicated large and established solid tumors of natural heterogeneity. CD4TCR-therapy targeted a mutant neoantigen on tumor stroma while direct cancer cell recognition by CD8TCR-therapy was essential for cure. Thus, two cancer-specific TCRs can be essential and sufficient to eradicate heterogeneous solid tumors expressing unmanipulated, autochthonous neoantigens. Citation Format: Steven Wolf, Vasiliki Anastasopoulou, Kimberley Drousch, Markus Diehl, Boris Engels, Poh Yin Yew, Kazuma Kiyotani, Yusuke Nakamura, Karin Schreiber, Hans Schreiber, Matthias Leisegang. Adoptive transfer of one CD4TCR and one CD8TCR targeting autochthonous neoantigens are essential and sufficient for eradication of naturally heterogeneous solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB073.