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1.
Cancer Cell ; 41(11): 1989-2005.e9, 2023 11 13.
Article in English | MEDLINE | ID: mdl-37802055

ABSTRACT

Identifying the cells from which cancers arise is critical for understanding the molecular underpinnings of tumor evolution. To determine whether stem/progenitor cells can serve as cells of origin, we created a Msi2-CreERT2 knock-in mouse. When crossed to CAG-LSL-MycT58A mice, Msi2-CreERT2 mice developed multiple pancreatic cancer subtypes: ductal, acinar, adenosquamous, and rare anaplastic tumors. Combining single-cell genomics with computational analysis of developmental states and lineage trajectories, we demonstrate that MYC preferentially triggers transformation of the most immature MSI2+ pancreas cells into multi-lineage pre-cancer cells. These pre-cancer cells subsequently diverge to establish pancreatic cancer subtypes by activating distinct transcriptional programs and large-scale genomic changes, and enforced expression of specific signals like Ras can redirect subtype specification. This study shows that multiple pancreatic cancer subtypes can arise from a common pool of MSI2+ cells and provides a powerful model to understand and control the programs that shape divergent fates in pancreatic cancer.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Mice , Animals , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/pathology
2.
Nat Commun ; 14(1): 292, 2023 01 18.
Article in English | MEDLINE | ID: mdl-36653361

ABSTRACT

Pancreatic cancer is characterized by extensive resistance to conventional therapies, making clinical management a challenge. Here we map the epigenetic dependencies of cancer stem cells, cells that preferentially evade therapy and drive progression, and identify SWI/SNF complex member SMARCD3 as a regulator of pancreatic cancer cells. Although SWI/SNF subunits often act as tumor suppressors, we show that SMARCD3 is amplified in cancer, enriched in pancreatic cancer stem cells and upregulated in the human disease. Diverse genetic mouse models of pancreatic cancer and stage-specific Smarcd3 deletion reveal that Smarcd3 loss preferentially impacts established tumors, improving survival especially in context of chemotherapy. Mechanistically, SMARCD3 acts with FOXA1 to control lipid and fatty acid metabolism, programs associated with therapy resistance and poor prognosis in cancer. These data identify SMARCD3 as an epigenetic modulator responsible for establishing the metabolic landscape in aggressive pancreatic cancer cells and a potential target for new therapies.


Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Humans , Mice , Animals , Transcription Factors/genetics , Transcription Factors/metabolism , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Epigenesis, Genetic , Pancreatic Neoplasms
3.
Trends Cancer ; 7(7): 624-634, 2021 07.
Article in English | MEDLINE | ID: mdl-33509688

ABSTRACT

Despite gains in knowledge of the intrinsic signals governing cancer progression, effective clinical management of cancer remains a challenge. Drug resistance and relapse, pose the greatest barriers to cancer care, and are often driven by the co-option of stem cell programs by subpopulations of aggressive cancer cells. Here, we focus on the role of the microenvironment in the acquisition and/or maintenance of stem cell states in cancer in the context of resistance and metastasis. We further discuss the role of cancer stem cells in immune evasion through the course of metastasis, dormancy, and relapse. Understanding the niche in which cancer stem cells live and the signals that sustain them may lead to new strategies that target them by disrupting microenvironmental support.


Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasm Recurrence, Local/immunology , Neoplasms/immunology , Neoplastic Stem Cells/pathology , Tumor Escape , Antineoplastic Agents/pharmacology , Cell Differentiation/immunology , Disease Progression , Drug Resistance, Neoplasm/immunology , Humans , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/prevention & control , Neoplasms/drug therapy , Neoplasms/pathology , Neoplastic Stem Cells/immunology , Signal Transduction/immunology , Tumor Microenvironment/immunology
4.
Food Chem ; 302: 125290, 2020 Jan 01.
Article in English | MEDLINE | ID: mdl-31404873

ABSTRACT

In our daily lives, we consume foods that have been transported, stored, prepared, cooked, or otherwise processed by ourselves or others. Food storage and preparation have drastic effects on the chemical composition of foods. Untargeted mass spectrometry analysis of food samples has the potential to increase our chemical understanding of these processes by detecting a broad spectrum of chemicals. We performed a time-based analysis of the chemical changes in foods during common preparations, such as fermentation, brewing, and ripening, using untargeted mass spectrometry and molecular networking. The data analysis workflow presented implements an approach to study changes in food chemistry that can reveal global alterations in chemical profiles, identify changes in abundance, as well as identify specific chemicals and their transformation products. The data generated in this study are publicly available, enabling the replication and re-analysis of these data in isolation, and serve as a baseline dataset for future investigations.


Subject(s)
Beverages/analysis , Food Analysis , Food Handling , Mass Spectrometry , Metabolomics , Fermentation , Workflow
5.
Cell ; 177(3): 572-586.e22, 2019 04 18.
Article in English | MEDLINE | ID: mdl-30955884

ABSTRACT

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.


Subject(s)
Adenocarcinoma/pathology , Neoplastic Stem Cells/metabolism , Pancreatic Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Animals , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cell Differentiation , Epigenesis, Genetic , Gene Library , Humans , Mice , Mice, Knockout , Mice, SCID , Neoplastic Stem Cells/cytology , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Interleukin-10/antagonists & inhibitors , Receptors, Interleukin-10/genetics , Receptors, Interleukin-10/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transcriptome , Tumor Cells, Cultured
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