tbuckley/cabot-search huggingface dataset:
Abstract A062: Somatic engineering of rat models to recapitulate human breast cancer evolution and heterogeneity
Authors: Catrin Lutz, Ji-Ying Song, Hendrik A Messal, Madelon Badoux, Timo Eijkman, Bim de Klein, Jelle Wesseling, Jos Jonkers
Journal: Cancer Research (2024)

Abstract Estrogen receptor (ER) positive breast cancer accounts for over 75% of all presenting clinical cases. In addition, almost all Ductal Carcinoma in situ (DCIS) lesions, now accounting for about 25% of all newly diagnosed ‘breast cancers’, are ER-dependent. Despite the high occurrence, the molecular underpinnings regulating DCIS initiation and progression to invasive disease remain elusive. This gap in knowledge is primarily due to the dearth of suitable preclinical models that accurately emulate breast cancer heterogeneity. To overcome this impediment, we developed a platform of somatic models by engineering the rat mammary gland and manipulating the genes most frequently mutated in hormone-dependent (pre-)breast cancer. This has successfully led to the generation of ER-positive disease models that provide a nuanced understanding of ER functionality and the complex mechanisms of ER signaling, which we show to be dependent on the cancer genotype. This has potential implications for the formulation of innovative endocrine therapy treatment regimens. Our models have generated an array of tumor types, including ductal and lobular carcinomas, manifesting both in situ and invasive phenotypes, faithfully recapitulating human breast disease and the evolution of tumorigenesis. Intriguingly, our results indicate how different oncogenic mutations modulate not only the architectural and histopathological characteristics of cancer but also the immune microenvironment, thereby generating possibilities for future therapeutic testing. Our research augments the range of available ER-positive in situ and invasive breast cancer models, benefitting the stratification of indolent from aggressive disease and facilitating the exploration of novel treatment strategies for this pervasive breast cancer subtype. Citation Format: Catrin Lutz, Ji-Ying Song, Hendrik A Messal, Madelon Badoux, Timo Eijkman, Bim de Klein, Jelle Wesseling, Jos Jonkers. Somatic engineering of rat models to recapitulate human breast cancer evolution and heterogeneity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A062.
Abstract IA15: Single cell origins and targeting of genomic instability in breast cancers
Authors: Samuel Aparicio
Journal: Cancer Research (2024)

Abstract Early whole genome sequencing studies have emphasised the different modes by which breast cancers can evolve. However, bulk NGS tissue analysis obscures mutations that are contemporaneous and/or lead to negative selection, and does not resolve clone specific metrics such as replication rate and fitness. We have developed single cell genome sequencing methods (Laks et al., Cell 2019) to identify large scale copy number-structural (CNA-SV) mutational processes that result in genomic shuffling through the duplication or deletion of chromosomal regions, obscured by bulk tissue analysis. This has revealed the existence and activity of distinct “foreground” mutational processes, i.e. mutational events in single mitoses that are observed directly, before the effects of purifying selection. We discovered that foreground processes are preferentially associated with background patterns of genome instability (Funnell et al., Nature 2022). We also discovered that CNA-SV mutational patterns are associated with relative sensitivity or resistance to platinum, a commonly used DNA targeting agent in TNBC and HGSOC. Our second recent discovery has been the association of CNA-SV mutations with clonal resistance to platinum in TNBC (Salehi et al., Nature 2021). Taken together, we now understand that ongoing CNA-SV mutations contribute to the evolution of fitness landscapes for DNA targeting therapeutics. In parallel work (Xu et al Nat. comms 2017) we have discovered stabilisers of folded DNA guanine stacked bases, G-quadruplexes (G4), to be synthetically lethal in contexts including HR and TMEJ that are underpinned by the single cell processes identified through single genome sequencing. To this end we have recently observed G4-ligand clinical activity in BRCA2 and PALB2 mutated cancers in a phase 1 trial (Hilton et al, Nature communication 2022). Citation Format: Samuel Aparicio. Single cell origins and targeting of genomic instability in breast cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA15.
Abstract A089: Role of Vardhamana Pippali Rasayana (VPR) in human breast cancer cells
Authors: Dr.Richa Tripathi, Shivam Singh, Subhash Gupta, VG Huddar, Tanuja M Nesari, Ashok Sharma
Journal: Cancer Research (2024)

Abstract Serious concerns include delayed diagnosis and adverse side-effects of conventional treatment leading to residual morbidity in Breast cancer (BC) globally. Traditional Indian medicines/herbs via combination of conventional cancer are gaining increasing acceptance worldwide, playing a pivotal role as proven by their efficacy evaluation studies. Many plants are known to reduce the cell proliferation and tumor development after their treatment. Vardhamana Pippali Rasayana (VPR), an Ayurvedic herbal preparation of pippali (Piper longum) in gradually increasing and tapering dose is used to treat many cancers without any adverse side-effects. However, its anti-cancer role in breast cancer is not known yet. The present study has explored the cytotoxic and apoptotic effects of VPR in triplicates on human breast cancer (MCF7) and normal breast epithelial (MCF10A) cell lines at different concentrations after extracting piperine in aqueous and hydro-alcoholic soxhlet extract (0.25 to 50 μg/μl). The cytotoxic activity was carried out by MTT assay and results showed that a low IC50 was observed at 3.75 μg/μl of VPR against MCF-7 as compared with normal breast epithelial cells. Detection of apoptotic cells using suitable Annexin V was done and there was a time-dependent increase in percentage of annexin V positive cells upon treatment. The above results indicate that VPR may have a strong anti-cancerous potential. But other functional assays are warranted to validate the efficacy of the drug against breast cancer which are under progress in our laboratory. Citation Format: Dr.Richa Tripathi, Shivam Singh, Subhash Gupta, VG Huddar, Tanuja M Nesari, Ashok Sharma. Role of Vardhamana Pippali Rasayana (VPR) in human breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A089.
Abstract IA006: Leveraging the extreme selection induced by therapeutic bottlenecks to subvert resistance via identifying evolutionarily-informed targets for orthogonal immunotherapy
Authors: J. Nic Fisk, Katerina Politi, Scott Gettinger, Jeffrey P Townsend
Journal: Cancer Research (2024)

Abstract Evolutionary dynamics underlie carcinogenesis, with tumor cells constantly adapting, resulting in cell populations that outgrow their non-tumor cell neighbors, evade treatment, and ultimately lead to death. Well-designed therapies to treating cancer induce immense and specific selection. The heterogenous cancer cell population either goes extinct or continues to evolve during and in response to the therapeutically induced bottleneck, leading to a subsequent selective sweep and newfound prominence of cells exhibiting the resistance phenotype. However, this bottleneck period provides a unique opportunity wherein the diversity of cells constituting the tumor is predictably reduced. Here, we introduce a framework to quantify the selection upon variants before, during, and after the therapeutic bottleneck, facilitating richer understanding of the mechanisms by which therapeutic resistance is acquired. We additionally couple measures of selection intensity with the prediction of neoantigens in a cohort of patients to identify potential orthogonal targets for immunotherapy. The result is a schema for leveraging predictability induced by the primary therapeutic bottleneck to drive the remnant tumor cell population to extinction. Finally, we demonstrate the utility of this schema in mutant EGFR lung adenocarcinoma. Citation Format: J. Nic Fisk, Katerina Politi, Scott Gettinger, Jeffrey P Townsend. Leveraging the extreme selection induced by therapeutic bottlenecks to subvert resistance via identifying evolutionarily-informed targets for orthogonal immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA006.
Abstract B053: The role of whole genome doubling in immune escape in TNBC
Authors: Pierre Foidart, Zheqi Li, Marco Seehawer, Jun Nishida, Ernesto Rojas, Triet Bui, Pengze Yan, Marie-Anne Goyette, Laura Stevens, Xiao-Yun Huang, Jayati Anand, Gouri Nanjangud, Yingtian Xie, Xintao Qiu, Paloma Cejas, Henry Long, Kornelia Polyak
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancers (TNBC) account for 10-15% of all breast cancers. The combination of chemotherapy and immune checkpoint inhibitor (ICI) therapy is now a standard in stage II-III TNBC while this regimen is used only in a subset of advanced TNBC tumors with high expression of PD-L1. Whole exome sequencing of solid tumors (other than breast cancer) in clinical trials investigating ICI determined that tumors which undergone a WGD (whole genome doubling) are more sensitive to immune checkpoints inhibitors, but the underlying mechanisms have not been defined. WGD occurs in 44% of breast cancers and it has been associated with advanced stage, poor survival, and higher risk of resistance to chemotherapies and targeted therapies. However, its role in response to ICI treatment in TNBC has not been investigated. To investigate the functional relevance of WGD in therapeutic responses in TNBC, we generated isogenic cell line pairs (3 murine and 1 human) that are diploid/euploid (WGD-) or tetraploid (WGD+) using somatic cell fusion. To explore the impact of WGD on tumor growth, we injected parental (WGD-) and fusion (WGD+) cells into mammary fat pads of syngeneic immunocompetent or immunocompromised (NSG) mice. We found that while there was no difference in growth between parental (WGD-) and fusion (WGD+) cells in immune deficient mice, in immunocompetent mice tumors derived from fusion (WGD+) cells grew significantly faster compared to parental (WGD-). We have been analyzing differences between parantel and fusion cell-derived tumos using FACS, immunofluorescence, and single cell RNA-seq (scRNA-seq) and found significant immune-related differences implying a more immune suppressive environment in fusion tumors. These data suggest that WGD in TNBC may be a predictor of response to ICI therapies. Citation Format: Pierre Foidart, Zheqi Li, Marco Seehawer, Jun Nishida, Ernesto Rojas, Triet Bui, Pengze Yan, Marie-Anne Goyette, Laura Stevens, Xiao-Yun Huang, Jayati Anand, Gouri Nanjangud, Yingtian Xie, Xintao Qiu, Paloma Cejas, Henry Long, Kornelia Polyak. The role of whole genome doubling in immune escape in TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B053.
Abstract B013: Understanding the anti-metastatic activity of estrogen receptor β in inflammatory breast cancer
Authors: Ilias Karagounis, Spyros Tastsoglou, Harika Nagandla, Naoto Ueno, Amit Maity, Artemis Hatzigeorgiou, Christoforos Thomas
Journal: Cancer Research (2024)

Abstract Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor a (ERα) negativity. We previously explored the second ER subtype, (ERβ) and reported expression in IBC tissues and correlation with reduced metastasis in patients. We have also seen decreased metastasis of IBC tumors in vivo when ERβ was expressed or activated by agonists. Mechanistically, we found that ablation of ERβ in IBC cells increased actin-based cell migration and activated gene expression that promote Rho GTP signaling and cytoskeleton reorganization. Because migratory cells undergo metabolic and epigenetic adaptations that enable them to evade immune surveillance and progress to metastasis, we have now followed an integrated approach to fully understand the role of ERβ as a driver of interconnected transcriptional programs that function to inhibit aggressive phenotypes. We have mapped ERβ binding sites in IBC cells and interrogated this information with gene expression data to identify downstream targets that prevent IBC cells from gaining metastatic traits. Through analysis of cells that express endogenous ERβ and upon its activation by agonists we have defined how a physiologically relevant receptor interacts with the cancer genome to adjust differentiation, metabolism and tumor host interactions to mitigate the metastatic propensity of IBC cells. We compared target genes in normal and malignant tissues and associated their expression with clinical outcomes to strengthen their biological relevance and evaluate their potential use as molecular targets. Our findings thus offer ample opportunities to advance our understanding about endocrine mechanisms that operate within the tumor microenvironment to regulate metastasis with the potential to discover novel targets for therapy intervention. Citation Format: Ilias Karagounis, Spyros Tastsoglou, Harika Nagandla, Naoto Ueno, Amit Maity, Artemis Hatzigeorgiou, Christoforos Thomas. Understanding the anti-metastatic activity of estrogen receptor β in inflammatory breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B013.
Abstract IA20: Hormonal action in breast cancer: Common features and unique properties that drive tumor development and outcome
Authors: Wilbert Zwart
Journal: Cancer Research (2024)

Abstract Estrogen receptor (ER) occupies many thousands of regions throughout the human genome. Interestingly, the functional implications of most of these chromatin-bound sites remain completely elusive. In two interconnected stories, I will highlight distinct genomic features that differentiate ER genomic action between patient subgroups, but also between individual patients. Between patients subgroups, we identify clearlty distinct profiles of ER action, dictated by Glucocorticoid Receptor (GR) activity. We show that the activity status of GR determines luminal subtype identity and is associated with patient outcome. GR suppresses tumor growth by engaging with ER, leading to redistribution of ER on the chromatin and upregulation of the tumor suppressor gene ZBTB16. We importantly demonstrate that clinically available epigenetic inhibitors, which mimic GR-induced gene repression, can effectively suppress the growth of highly aggressive ER-positive breast cancer cells displaying absence of GR activity. In a second study, I will elaborate on the massive inter-patient heterogeneity of ER chromatin interactions, with direct biological and clinical implications. While the vast majorty of ER/DNA binding events are poorly conserved between patients, common ER sites are most-transcriptionally active and enriched for breast cancer risk SNPs. With that, we present a natural hierarchy of ER genomic action, identifying those regiosn with the most-direct impact on breast cancer development and progresion. Citation Format: Wilbert Zwart. Hormonal action in breast cancer: Common features and unique properties that drive tumor development and outcome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA20.
Abstract PR02: Modeling breast cancer through somatic precision gene editing with high flexibility and efficiency
Authors: Wen Bu, Yi Li, Chad J Creighton, Kelsey S Heavener, Carolina Gutierrez, Yongchao Dou, Weiyu Jiang, Bing Zhang, Amy T Ku, Shixia Huang
Journal: Cancer Research (2024)

Abstract CRISPR/Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR/Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either Kras or Pik3ca in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less inter-tumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing. Citation Format: Wen Bu, Yi Li, Chad J Creighton, Kelsey S Heavener, Carolina Gutierrez, Yongchao Dou, Weiyu Jiang, Bing Zhang, Amy T Ku, Shixia Huang. Modeling breast cancer through somatic precision gene editing with high flexibility and efficiency [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR02.
Abstract B009: TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer
Authors: Yinghui Li, Nicholas Sim, Jean-Michel Carter, Kamalakshi Deka, Benita Kiat Tee Tan, Yirong Sim, Suet-Mien Tan
Journal: Cancer Research (2024)

Abstract Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from a lack of targeted treatment options. There is a high priority to identify effective molecular markers or driver factors specific to TNBC patients for targeted therapies. The Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14) pathway is one such signalling cascade implicated in the pathogenesis of TNBC and other solid tumours. However, the clinical significance and biological roles of deregulated TWEAK/Fn14 signalling in regulating the epigenetic plasticity and transcriptome of TNBCs remain elusive. In this study, we performed integrative transcriptomic and epigenomic analyses of TNBC cell lines and patient samples to characterise the gene regulatory roles of TWEAK/Fn14 pathway in remodelling the super-enhancer (SE) landscape of TNBC tumours. Here, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of NAMPT, which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients. Citation Format: Yinghui Li, Nicholas Sim, Jean-Michel Carter, Kamalakshi Deka, Benita Kiat Tee Tan, Yirong Sim, Suet-Mien Tan. TWEAK/Fn14 signalling driven super-enhancer reprogramming promotes pro-metastatic metabolic rewiring in Triple-Negative Breast Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B009.
Abstract B052: The role of LMO2 in DNA damage repair pathway choice in metastatic breast cancer
Authors: Isobel Fetter, Veronica Haro-Acosta, Shaheen Sikandar
Journal: Cancer Research (2024)

Abstract Introduction: Previously we discovered that a novel metastasis-initiating cell (MIC) population is marked by LMO2, a transcriptional adaptor protein in hematopoietic stem cells, and a T-cell oncogene. Knocking down LMO2 did not affect the growth of primary tumors, but did significantly reduce the number of circulating tumor cells and lung metastases. Transcriptional analysis of LMO2 knockdown shows the HALLMARK_DNA_REPAIR pathway is upregulated, suggesting that LMO2 is involved in regulating DNA repair in breast cancer cells. Interestingly, a previous study reported that in diffuse large B-cell lymphoma high LMO2 expression results in defective repair of double-stranded DNA breaks (Parvin et al., Cancer Cell, 36, 3 [2019]). We hypothesize that in breast cancer LMO2 expression is regulating the choice between homology-directed repair (HDR), an error-free method of DNA repair, and non-homologous end-joining (NHEJ), a more error-prone method. Cells that use NHEJ to repair DNA are dependent on poly (ADP-ribose) polymerase (PARP) and can be targeted with PARP inhibitors. LMO2 could thus be used as a new biomarker for benefit from PARP inhibition. Methods: LMO2 was identified using single-cell RNAseq data from human breast cancer patients. In vitro and in vivo assays using breast cancer cell lines and patient-derived xenografts were used to characterize the effect of LMO2 on metastasis. To study the role of LMO2 in the DNA damage response, we used MDA-MB-468 and HCC1806 cells with control and 2 independent shRNAs targeting LMO2. Immunofluorescent staining for γH2AX, 53BP1, and RAD51 was performed to measure changes in DNA damage and repair markers. Control and LMO2 knockdown cells were treated with olaparib, with cellular proliferation measured with a WST-1 assay and colony formation measured with crystal violet staining. Results and Conclusion: Knocking down LMO2 expression results in decreased NHEJ and increased HDR in MDA-MB-468 and HCC1806 cells. There is no significant difference in DNA damage overall as measured by γH2AX foci/nucleus. LMO2 knockdown in MDA-MB-468 cells reduces sensitivity to PARP inhibition with olaparib, as measured by an increase in the IC50 values. Our preliminary data suggest that LMO2 expression likely regulates the choice between NHEJ and HDR. LMO2 expression introduces a bias towards NHEJ, which sensitizes cells to PARP inhibition. This suggests that LMO2+ cells could be targeted with PARP inhibition, which could thus be used to target metastasis-initiating cells. Citation Format: Isobel Fetter, Veronica Haro-Acosta, Shaheen Sikandar. The role of LMO2 in DNA damage repair pathway choice in metastatic breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B052.