MUC1-C IS A MASTER REGULATOR OF SMALL CELL LUNG CANCER PROGRESSION
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE159801 | GEO | 2023/01/12
REPOSITORIES: GEO
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Project description:Small cell lung cancer (SCLC) is a recalcitrant malignancy associated with dysregulation of MYC signaling and the CDK-RB-E2F axis. We report that expression of the oncogenic MUC1-C protein in SCLC cells integrates activation of MYC and the E2F pathway. MUC1-C drives MYC and E2F target genes and regulates the G2/M checkpoint, mitotic spindle pathway and replication stress response (RSR). We further show that MUC1-C MYC signaling (i) induces NOTCH2, a marker of pulmonary neuroendocrine (NE) stem cells that are the proposed cell of SCLC origin, (ii) drives NE differentiation, as evidenced by expression of ASCL1 and POU3F2/BRN2, and (iii) promotes self-renewal capacity and tumorigenicity of SCLC cells. Analyses of datasets from SCLC tumors confirmed that MUC1 significantly associates with the MYC pathway. These findings uncover a master role for MUC1-C in promoting progression of the SCLC stem cell state and support MUC1-C as a potential target for SCLC treatment.
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Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.
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Project description:Distinct SCLC molecular subtypes have been defined based on expression of lineage-related transcription factors: ASCL1, NEUROD1, POU2F3 or YAP1, but their origins remain unknown. We perform bulk RNA-sequencing on SCLC tumors from RPM and Rb1/Trp53/Rbl2 (RPR2) GEMMs, initiated by CGRP-Cre, to complement time-series analysis of single-cell transcriptome profiling and reveal that MYC drives the dynamic evolution of SCLC subtypes. MYC promotes a temporal shift from an ASCL1-to-NEUROD1-to-YAP1+ state from a neuroendocrine cell of origin. MYC activates Notch signaling to dedifferentiate tumor cells to non-neuroendocrine fates. Sequenced RPM tumors driven by MycT58A, in comparison to RPR2 tumors associated with high Mycl, have increased intratumoral subtype heterogeneity by bulk-seq, single-cell RNA seq, and IHC compared to RPR2 tumors. In RPM tumors with high MYC, tumors are able to proceed to non-NE subtypes resembling the NEUROD1+ and YAP1+ human SCLC subtypes. These findings support our overall conclusions that genetics, cell of origin, and tumor cell plasticity determine SCLC subtype.
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Project description:Small cell lung cancer is the most aggressive type of lung cancer and has a high degree of plasticity, characterized by a remarkable response to chemotherapy followed by development of resistance. We show that intratumoral heterogeneity of SCLC is progressively established, indicated by the appearance of YAP+ and HES1+ SCLC tumor cells. Notch signaling is required for the generation of Non-NE SCLC cells, but not for the tumorigenesis of SCLC. Furthermore, YAP signals through Notch-dependent and independent pathway to induce REST expression to promote the conversion of NE to Non-NE SCLC tumor cells. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells by downregulating GSDME, while inactivation of YAP in Non-NE SCLC tumor cells switches cell death from apoptosis to pyroptosis. Our study will not only provide novel insights into the molecular basis of SCLC tumorigenesis, but also the potential drug targets for SCLC therapy
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Project description:Small cell lung cancer is the most aggressive type of lung cancer and has a high degree of plasticity, characterized by a remarkable response to chemotherapy followed by development of resistance. We show that intratumoral heterogeneity of SCLC is progressively established, indicated by the appearance of YAP+ and HES1+ SCLC tumor cells. Notch signaling is required for the generation of Non-NE SCLC cells, but not for the tumorigenesis of SCLC. Furthermore, YAP signals through Notch-dependent and independent pathway to induce REST expression to promote the conversion of NE to Non-NE SCLC tumor cells. In addition, YAP activation enhances the chemoresistance in NE SCLC tumor cells by downregulating GSDME, while inactivation of YAP in Non-NE SCLC tumor cells switches cell death from apoptosis to pyroptosis. Our study will not only provide novel insights into the molecular basis of SCLC tumorigenesis, but also the potential drug targets for SCLC therapy
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Project description:Intratumoral heterogeneity underlies cancer treatment resistance, but approaches to neutralize it remain elusive. Here, we recast heterogeneity in a systems perspective that considers cancer cell functional tasks inherited from cells of origin. We apply Archetype Analysis to bulk transcriptomics data from small cell lung cancer (SCLC), which forms tumors composed of neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. SCLC subtypes fit well in a 5-dimensional polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterpart, and include injury repair, slithering, and chemosensation. SCLC cells near a vertex are specialists for a task, while more distant cells are generalists, bearing gene signatures of multiple archetypes. Evolutionary theory and dynamical systems modeling suggest a division of labor strategy for adaptation to treatment, based on task trade-offs amongst specialists and generalists. Cell Transport Potential, a metric derived from single-cell RNA velocity, uncovers plasticity trends from specialists to generalists, and NE to non-NE subtypes. Transcription factor network simulations indicate that MYC overexpression increases plasticity by de-stabilizing NE subtypes. Framing heterogeneity in archetype space provides insights into transformative cancer treatments aimed at tumor cell plasticity.
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Project description:Intratumoral heterogeneity underlies cancer treatment resistance, but approaches to neutralize it remain elusive. Here, we recast heterogeneity in a systems perspective that considers cancer cell functional tasks inherited from cells of origin. We apply Archetype Analysis to bulk transcriptomics data from small cell lung cancer (SCLC), which forms tumors composed of neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. SCLC subtypes fit well in a 5-dimensional polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterpart, and include injury repair, slithering, and chemosensation. SCLC cells near a vertex are specialists for a task, while more distant cells are generalists, bearing gene signatures of multiple archetypes. Evolutionary theory and dynamical systems modeling suggest a division of labor strategy for adaptation to treatment, based on task trade-offs amongst specialists and generalists. Cell Transport Potential, a metric derived from single-cell RNA velocity, uncovers plasticity trends from specialists to generalists, and NE to non-NE subtypes. Transcription factor network simulations indicate that MYC overexpression increases plasticity by de-stabilizing NE subtypes. Framing heterogeneity in archetype space provides insights into transformative cancer treatments aimed at tumor cell plasticity.
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Project description:Enhanced RAF/MEK/ERK signaling plays an obligatory role in many different types of cancer. Although genetic lesions promoting its aberrant activation are found in lung adenocarcinoma (LADC), the biological role of this pathway is not well documented in small cell lung cancer (SCLC). Here we explored the role of this pathway in SCLC and the broader class of tumors with neuroendocrine (NE) differentiation by introducing a constitutively active form of Fibroblast growth factor receptor 1 (Fgfr1) together with biallelic inactivation of Rb1 and Trp53 in mouse lung. Our data show that FGFR1 expression primarily results in LADC but also in NE tumors depending on the cell-of-origin. FGFR1 activation selectively promoted NE bronchial lesions in a novel lung cell subpopulation, whereas it impaired progression of typical central SCLC initiated from CGRP-expressing NE cells, which is believed to be the most prominent cell-of-origin of SCLC. Strikingly, FGFR1 activation was well tolerated by K14-expressing cells that were efficiently transformed into SCLC and other NE lesions. Taken together, our results indicate that FGFR1 can serve either as driver or suppressor of distinct lung cancer subtypes depending on the cell-of-origin, which should be taken into account when considering FGFR1 as a therapeutic target.
2020-03-27 | GSE132759 | GEO
Project description:Lung cancer is the leading cause of cancer death in the United States. Among the various subtypes of lung cancers, pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC) and NE-non-small cell lung cancer (NE-NSCLC), is a particularly aggressive malignancy that is distinct from classic non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Recently, the lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1, and POU2F3 have been reported to identify heterogeneity in pulmonary NE cancers. These transcription factors bind different genomic loci to regulate distinct gene programs in pulmonary NE cancers. However, the signaling pathways downstream of these transcription factors that distinguish these pulmonary NE cancer subtypes are not well characterized. Regulated protein secretion is critically involved in cell signaling and cell-cell communication events, and is known to be a hallmark associated with pulmonary NE tumors. Using a large-scale mass spectrometric approach, we performed quantitative secretomic analysis 13 cell lines including a pair of isogenic cell lines, i.e., an immortalized human bronchial epithelial cell and an ASCL1high NE NSCLC line. This panel also contained 6 additional ASCL1High and 5 NEUROD1High NE-lung cancer cell lines. From the conditioned media of the 13 cell lines, we identified and quantified 1,626 proteins. The NE-specific secretome is associated with a number of biological processes related to neurodevelopment. Further analysis of the upregulated proteins in ASCL1High subtype NE-lung cancer cells leads to the identification of IGFBP5 being a specific secreted marker for ASCL1High pulmonary NE cancer cells. Furthermore, IGFBP5 is also upregulated in the serum of a genetically modified mouse model of ASCL1High SCLC, as well as in human ASCL1High SCLC tumors. Mechanistically, ASCL1 binds to E-box elements in the IGFBP5 gene and directly regulates its transcription. Knockdown of ASCL1 in SCLC decreases IGFBP5 expression, which, in turn, leads to hyperactivation of the IGF-1R pathway. Pharmacological co-targeting of ASCL1 and IGF-1R signaling results in markedly synergistic, growth inhibitory effects in ASCL1High SCLC both in vitro and in vivo. Together, our quantitative proteomic analysis identifies a novel secreted marker and a new combination therapy for ASCL1High pulmonary NE cancer cells. In addition, we expect that the data sets will serve as an invaluable resource, providing the foundation for future mechanistic studies and biomarker discovery that helps delineate the molecular underpinnings of pulmonary NE tumors.
2019-07-03 | PXD013298 | Pride
Project description:Lung cancer is the leading cause of cancer death in the United States. Among the various subtypes of lung cancers, pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC) and NE-non-small cell lung cancer (NE-NSCLC), is a particularly aggressive malignancy that is distinct from classic non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Recently, the lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1, and POU2F3 have been reported to identify heterogeneity in pulmonary NE cancers. These transcription factors bind different genomic loci to regulate distinct gene programs in pulmonary NE cancers. However, the signaling pathways downstream of these transcription factors that distinguish these pulmonary NE cancer subtypes are not well characterized. Regulated protein secretion is critically involved in cell signaling and cell-cell communication events, and is known to be a hallmark associated with pulmonary NE tumors. Using a large-scale mass spectrometric approach, we performed quantitative secretomic analysis 13 cell lines including a pair of isogenic cell lines, i.e., an immortalized human bronchial epithelial cell and an ASCL1high NE NSCLC line. This panel also contained 6 additional ASCL1High and 5 NEUROD1High NE-lung cancer cell lines. From the conditioned media of the 13 cell lines, we identified and quantified 1,626 proteins. The NE-specific secretome is associated with a number of biological processes related to neurodevelopment. Further analysis of the upregulated proteins in ASCL1High subtype NE-lung cancer cells leads to the identification of IGFBP5 being a specific secreted marker for ASCL1High pulmonary NE cancer cells. Furthermore, IGFBP5 is also upregulated in the serum of a genetically modified mouse model of ASCL1High SCLC, as well as in human ASCL1High SCLC tumors. Mechanistically, ASCL1 binds to E-box elements in the IGFBP5 gene and directly regulates its transcription. Knockdown of ASCL1 in SCLC decreases IGFBP5 expression, which, in turn, leads to hyperactivation of the IGF-1R pathway. Pharmacological co-targeting of ASCL1 and IGF-1R signaling results in markedly synergistic, growth inhibitory effects in ASCL1High SCLC both in vitro and in vivo. Together, our quantitative proteomic analysis identifies a novel secreted marker and a new combination therapy for ASCL1High pulmonary NE cancer cells. In addition, we expect that the data sets will serve as an invaluable resource, providing the foundation for future mechanistic studies and biomarker discovery that helps delineate the molecular underpinnings of pulmonary NE tumors.
2019-07-22 | PXD013267 | Pride