71 results on '"Kwan Ho Tang"'
Search Results
2. Data from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
- Author
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Benjamin G. Neel, Alireza Khodadadi-Jamayran, Benjamin Haibe-Kains, Abhyudai Singh, Jason Moffat, Beatrix Ueberheide, Aristotelis Tsirigos, Jane A. Skok, Adriana Heguy, Peter Meyn, Sylvia Adams, Kwok-kin Wong, Jiehui Deng, Christos Sotiriou, David Venet, Kwan Ho Tang, Avantika Dhabaria, Allison M.L. Nixon, Kevin R. Brown, Arvind Singh Mer, Azin Sayad, Shaowen Jiang, Jayu Jen, and Chewei Anderson Chang
- Abstract
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. “Drug-tolerant persisters” (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a “pre-DTP” state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor–dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.Significance:DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells (“pre-DTPs”) that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities.This article is highlighted in the In This Issue feature, p. 873
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- 2023
3. Supplementary Table from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
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Benjamin G. Neel, Alireza Khodadadi-Jamayran, Benjamin Haibe-Kains, Abhyudai Singh, Jason Moffat, Beatrix Ueberheide, Aristotelis Tsirigos, Jane A. Skok, Adriana Heguy, Peter Meyn, Sylvia Adams, Kwok-kin Wong, Jiehui Deng, Christos Sotiriou, David Venet, Kwan Ho Tang, Avantika Dhabaria, Allison M.L. Nixon, Kevin R. Brown, Arvind Singh Mer, Azin Sayad, Shaowen Jiang, Jayu Jen, and Chewei Anderson Chang
- Abstract
Supplementary Table from Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
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- 2023
4. Supplementary table and figure legends from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
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Kwan Ho Tang, Benjamin G. Neel, George Miller, Diane M. Simeone, Ugur Ozerdem, Kiyomi Araki, Mitchell J. Geer, Jayu Jen, Wei Wei, Brian Diskin, Hao Ran, and Carmine Fedele
- Abstract
Supplementary table and figure legends
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- 2023
5. Data from Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
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Benjamin G. Neel, Kwok-Kin Wong, Aristotelis Tsirigos, Cynthia A. Loomis, Argus Athanas, Peter Olson, James G. Christensen, Dean Y. Maeda, John A. Zebala, Carmine Fedele, Yuan Hao, Ting Chen, Kayla Guidry, Han Han, Jayu Jen, Alireza Khodadadi-Jamayran, Shuai Li, and Kwan Ho Tang
- Abstract
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non–small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9hi gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC.Significance:Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NFκB-dependent upregulation of CXCR2 ligands and recruitment of S100A8hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8+KLRG1+ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models.This article is highlighted in the In This Issue feature, p. 1
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- 2023
6. Supplementary Table S1 from Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations
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Xin-Yuan Guan, Bo-Jian Zheng, Jana Yim-Hung Wo, Kwan Ho Tang, Terence Kin-Wah Lee, Kwok Wah Chan, and Stephanie Ma
- Abstract
Supplementary Table S1 from Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations
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- 2023
7. Table S7 from Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
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Benjamin G. Neel, Kwok-Kin Wong, Aristotelis Tsirigos, Cynthia A. Loomis, Argus Athanas, Peter Olson, James G. Christensen, Dean Y. Maeda, John A. Zebala, Carmine Fedele, Yuan Hao, Ting Chen, Kayla Guidry, Han Han, Jayu Jen, Alireza Khodadadi-Jamayran, Shuai Li, and Kwan Ho Tang
- Abstract
Table S7
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- 2023
8. Table S1 and S2 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
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Kwan Ho Tang, Benjamin G. Neel, George Miller, Diane M. Simeone, Ugur Ozerdem, Kiyomi Araki, Mitchell J. Geer, Jayu Jen, Wei Wei, Brian Diskin, Hao Ran, and Carmine Fedele
- Abstract
Table S1: Bliss Index for Effect of MEK-I/SHP099 Combination on Cancer Cell Proliferation Table S2: Primer Sequences for qRT-PCR
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- 2023
9. Figure S1-6 from Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
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Benjamin G. Neel, Kwok-Kin Wong, Aristotelis Tsirigos, Cynthia A. Loomis, Argus Athanas, Peter Olson, James G. Christensen, Dean Y. Maeda, John A. Zebala, Carmine Fedele, Yuan Hao, Ting Chen, Kayla Guidry, Han Han, Jayu Jen, Alireza Khodadadi-Jamayran, Shuai Li, and Kwan Ho Tang
- Abstract
Figure S1-6
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- 2023
10. Figure S1-S7 from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
- Author
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Kwan Ho Tang, Benjamin G. Neel, George Miller, Diane M. Simeone, Ugur Ozerdem, Kiyomi Araki, Mitchell J. Geer, Jayu Jen, Wei Wei, Brian Diskin, Hao Ran, and Carmine Fedele
- Abstract
Supplementary Figure S1: Combined SHP2/MEK inhibition prevents adaptive resistance in PDAC and NSCLC lines Supplementary Figure S2: SHP2 inhibition abrogates MEK-I-evoked reactivation of the ERK MAPK pathway Supplementary Figure S3: Distinct mechanisms of resistance to MEK-I/SHP099 combination in PDAC lines Supplementary Figure S4: Development of tolerable SHP099/trametinib regimen Supplementary Figure S5: Combination decreases tumor cell proliferation and promotes programmed cell death (PDAC and NSCLC) Supplementary Figure S6: Combination decreases tumor cell proliferation and promotes programmed cell death (PDAC, TNBC and HGSC) Supplementary Figure S7: RTKs/RTK ligand expression and Annexin V/cell cycle analysis of TNBC and HGSC lines
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- 2023
11. Supplementary Method from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
- Author
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Kwan Ho Tang, Benjamin G. Neel, George Miller, Diane M. Simeone, Ugur Ozerdem, Kiyomi Araki, Mitchell J. Geer, Jayu Jen, Wei Wei, Brian Diskin, Hao Ran, and Carmine Fedele
- Abstract
Detailed Supplementary Method
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- 2023
12. Data from Aldehyde Dehydrogenase Discriminates the CD133 Liver Cancer Stem Cell Populations
- Author
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Xin-Yuan Guan, Bo-Jian Zheng, Jana Yim-Hung Wo, Kwan Ho Tang, Terence Kin-Wah Lee, Kwok Wah Chan, and Stephanie Ma
- Abstract
Recent efforts in our study of cancer stem cells (CSC) in hepatocellular carcinoma (HCC) have led to the identification of CD133 as a prominent HCC CSC marker. Findings were based on experiments done on cell lines and xenograft tumors where expression of CD133 was detected at levels as high as 65%. Based on the CSC theory, CSCs are believed to represent only a minority number of the tumor mass. This is indicative that our previously characterized CD133+ HCC CSC population is still heterogeneous, consisting of perhaps subsets of cells with differing tumorigenic potential. We hypothesized that it is possible to further enrich the CSC population by means of additional differentially expressed markers. Using a two-dimensional PAGE approach, we compared protein profiles between CD133+ and CD133− subpopulations isolated from Huh7 and PLC8024 and identified aldehyde dehydrogenase 1A1 as one of the proteins that are preferentially expressed in the CD133+ subfraction. Analysis of the expression of several different ALDH isoforms and ALDH enzymatic activity in liver cell lines found ALDH to be positively correlated with CD133 expression. Dual-color flow cytometry analysis found the majority of ALDH+ to be CD133+, yet not all CD133+ HCC cells were ALDH+. Subsequent studies on purified subpopulations found CD133+ALDH+ cells to be significantly more tumorigenic than their CD133−ALDH+ or CD133−ALDH− counterparts, both in vitro and in vivo. These data, combined with those from our previous work, reveal the existence of a hierarchical organization in HCC bearing tumorigenic potential in the order of CD133+ALDH+ > CD133+ALDH− > CD133−ALDH−. ALDH, expressed along CD133, can more specifically characterize the tumorigenic liver CSC population. (Mol Cancer Res 2008;6(7):1146–53)
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- 2023
13. Table S2 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
GSEA analysis of mobocertinib and T-DM1 treated tumors versus mobocertinib-only treated tumors Genes involved in "INTERFERON ALPHA RESPONSE", "INFLAMMATORY RESPONSE", "INTERFERON GAMMA RESPONSE", "IL2 STAT5 SIGNALING", "TNFA SIGNALING VIA NFKB" and "IL6 JAK STAT3 SIGNALING" pathways of HALLMARK gene sets.
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- 2023
14. Data from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.Significance:This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
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- 2023
15. Figure S1 from Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
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Kwok-Kin Wong, Sylvie Vincent, Rachael Brake, Victor M. Rivera, Haiquan Chen, Francois Gonzalvez, Sittinon Tang, Eleni Papadopoulos, Cassandra Thakurdin, Val Pyon, Hai Hu, Hailin Ding, Yuanwang Pan, Hua Zhang, Fei Li, Theresa E. Baker, Zhendong Gao, Jiehui Deng, David Peng, Jiansheng Wu, Johara Chouitar, Shougen Cao, Kwan Ho Tang, Chengwei Peng, Shengwu Liu, Michael Fitzgerald, Ting Chen, Shuai Li, and Han Han
- Abstract
Figure S1
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- 2023
16. Supplementary Figure 1 from A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer
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Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Simon Law, Daniel K. Tong, Maria L. Lung, Hong Lok Lung, Sai Wah Tsao, Yan Ru Qin, Li Fu, Pak Shing Kwan, Yuen Piu Chan, Man Tong, Yong Dong Dai, and Kwan Ho Tang
- Abstract
PDF file - 490K, Supplemental Figure 1. A significantly deregulated network of genes in CD90+ esophageal T-ICs identified by genome-wide expression profiling and Ingenuity Pathway Analysis (IPA).
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- 2023
17. Supplementary Table 2 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary Table 2 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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- 2023
18. Data from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3′UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer. Cancer Res; 71(2); 583–92. ©2011 AACR.
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- 2023
19. Supplementary Figure 2 from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
PDF file, 720K, Detection of DNA copy number change of Rab25 by dual-color fluorescent in situ hybridization (FISH) in ESCC cell lines KYSE520, EC109 and formalin-fixed paraffin-embedded ESCC clinical tissue specimens (#1 and #2) with no or low Rab25 expression. BAC probe to Rab25 and the control reference probe to the centromere of chromosome 1 are represented by red and green signals, respectively. Magnification at 1000x.
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- 2023
20. Supplementary Information from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
PDF file, 153K, Supplementary Materials and Methods, Tables, Figure Legends, References
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- 2023
21. Supplementary Figure Legend and Table 1 - 5 from A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer
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Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Simon Law, Daniel K. Tong, Maria L. Lung, Hong Lok Lung, Sai Wah Tsao, Yan Ru Qin, Li Fu, Pak Shing Kwan, Yuen Piu Chan, Man Tong, Yong Dong Dai, and Kwan Ho Tang
- Abstract
DOC file - 322K, Supplemental Table 1. Primer sequences for real-time qPCR analyses. Supplemental Table 2. RPKM values of other reported CSC markers in the original 3 pairs of non-tumor (N) and ESCC (T) clinical samples (Patients #16, #18 and #19) used for RNA-Seq profiling. Supplemental Table 3. Cancer stem cell marker expression (CD90, CD44 and p75NTR / CD271) in a panel of ESCC cell lines. Supplemental Table 4. Clinicopathological correlation of CD44 and p75NTR / CD271 expression in ESCC. Supplemental Table 5. List of deregulated genes in CD90+ vs. CD90- cells in ESCC cells KYSE140 (cut off ≥ 3 folds).
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- 2023
22. Supplementary Figure 2 from A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer
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Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Simon Law, Daniel K. Tong, Maria L. Lung, Hong Lok Lung, Sai Wah Tsao, Yan Ru Qin, Li Fu, Pak Shing Kwan, Yuen Piu Chan, Man Tong, Yong Dong Dai, and Kwan Ho Tang
- Abstract
PDF file - 1414K, Supplemental Figure 2. CD90, CD44 and p75NTR / CD271 expression in matched non-tumor (N) and primary ESCC (T) (n = 33) as detected by real-time qPCR.
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- 2023
23. Supplementary Figure Legend from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary Figure Legend from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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- 2023
24. Data from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK–Raf–MEK1/2–ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024–35. ©2012 AACR.
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- 2023
25. Supplementary Figure 1 from Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
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Stephanie Ma, Xin-Yuan Guan, Si Lok, Yan-Ru Qin, Li Fu, Kwan Ho Tang, Pak Shing Kwan, Jin-Na Chen, Kai Yau Wong, Jessie Y.J. Bao, Kwok Wah Chan, and Man Tong
- Abstract
PDF file, 2272K, Expression tiling of Rab25 in 6 unpaired ESCC and non-tumor clinical samples.
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- 2023
26. Supplementary Figure 1 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary Figure 1 from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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- 2023
27. Supplementary References from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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Kwok Wah Chan, Xin-Yuan Guan, Juergen R. Vielkind, Ming Tat Ling, Kwan Ho Tang, Mingxia Yan, Terence K. Lee, Pak Shing Kwan, Yuen Piu Chan, and Stephanie Ma
- Abstract
Supplementary References from MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
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- 2023
28. Targeting HER2 Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
- Author
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Hua Zhang, Haiquan Chen, Sittinon Tang, Shougen Cao, Yuanwang Pan, Victor M. Rivera, Shuai Li, Fei Li, Kwan Ho Tang, Hai Hu, Chengwei Peng, Francois Gonzalvez, Hailin Ding, Jiehui Deng, Johara Chouitar, Han Han, Sylvie Vincent, Theresa E. Baker, Michael Fitzgerald, Val Pyon, Ting Chen, Zhendong Gao, Rachael L. Brake, Eleni Papadopoulos, David H. Peng, Jiansheng Wu, Cassandra Thakurdin, Kwok-Kin Wong, and Shengwu Liu
- Subjects
Cancer Research ,medicine.drug_class ,Afatinib ,T cell ,Poziotinib ,Biology ,medicine.disease ,Tyrosine-kinase inhibitor ,Exon ,medicine.anatomical_structure ,Oncology ,Neratinib ,medicine ,Cancer research ,Adenocarcinoma ,skin and connective tissue diseases ,Lung cancer ,medicine.drug - Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
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- 2021
29. Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
- Author
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Argus Athanas, Kwok-Kin Wong, John A Zebala, Carmine Fedele, Han Han, Yuan Hao, Kwan Ho Tang, Kayla Guidry, James G. Christensen, Benjamin G. Neel, Aristotelis Tsirigos, Dean Y. Maeda, Alireza Khodadadi-Jamayran, Cynthia Loomis, Ting Chen, Peter D. Olson, Shuai Li, and Jayu Jen
- Subjects
Male ,MAPK/ERK pathway ,Lung Neoplasms ,Antineoplastic Agents ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,medicine.disease_cause ,Receptors, Interleukin-8B ,Article ,CCL5 ,Mice ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Animals ,Humans ,CXCL10 ,Cytotoxic T cell ,Enzyme Inhibitors ,Receptor ,Tumor microenvironment ,Chemistry ,Xenograft Model Antitumor Assays ,respiratory tract diseases ,Mice, Inbred C57BL ,Oncology ,Cancer research ,KRAS ,CD8 - Abstract
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non–small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9hi gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC. Significance: Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NFκB-dependent upregulation of CXCR2 ligands and recruitment of S100A8hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8+KLRG1+ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models. This article is highlighted in the In This Issue feature, p. 1
- Published
- 2021
30. Dual inhibition of SHP2 and autophagy suppresses NF1-associated Malignant Peripheral Nerve Sheath Tumors
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Sameer Farouk Sait, Kwan-ho Tang, Steve Angus, Rebecca Brown, Daochun Sun, Xuanhua Xie, Charlene Iltis, Michelle Lien, Nicholas Socci, Tejus Bale, Christopher Davis, Shelley A.H Dixon, Chi Zhang, D. Wade Clapp, Benjamin G. Neel, and Luis F. Parada
- Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas and the primary cause of mortality in patients with neurofibromatosis type 1 (NF1). MPNSTs develop within pre-existing benign plexiform neurofibromas (PNs). PNs are driven solely by biallelic NF1 loss eliciting RAS pathway activation and respond favorably to MEK inhibitor therapy. Our analysis of genetically engineered and orthotopic patient-derived xenograft MPNST indicates that MEK inhibition has poor anti-tumor efficacy. By contrast, upstream inhibition of RAS through the protein-tyrosine phosphatase SHP2 reduced downstream signaling and suppressed NF1 MPNST growth, although resistance eventually emerged. To investigate possible mechanisms of acquired resistance, kinomic analyses of resistant tumors was performed, and data analysis identified enrichment of activated autophagy pathway protein kinases. Combining pharmacological blockade of autophagy and SHP2 inhibition resulted in durable responses in NF1 MPNSTs in both genetic and orthotopic xenograft mouse models. Our studies can be rapidly translated into a clinical trial to evaluate SHP2 inhibition in conjunction with autophagy inhibitors as a novel treatment approach for NF1 MPNSTs.Statement of significanceCurrently, no effective therapies exist for MPNST. We demonstrate intrinsic MPNST resistance to MEKi monotherapy and identify SHP2 inhibition as an actionable vulnerability upstream of RAS. Furthermore, anti-tumor effects are extended and enhanced by dual exposure to autophagy pathway inhibition. Validation of these results as the most effective therapy to date in multiple genetically engineered models and in orthotopic patient-derived xenografts justify a clinical trial to evaluate SHP2i in conjunction with autophagy inhibitors as a novel treatment approach for NF1 MPNSTs.
- Published
- 2022
31. Drug-induced adaptation along a resistance continuum in cancer cells
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Gustavo S. França, Maayan Baron, Maayan Pour, Benjamin R. King, Anjali Rao, Selim Misirlioglu, Dalia Barkley, Igor Dolgalev, Kwan Ho-Tang, Gal Avital, Felicia Kuperwaser, Ayushi Patel, Douglas A. Levine, Timothee Lionnet, and Itai Yanai
- Abstract
Advancements in rational drug design over the past decades have consistently produced new cancer therapies, but such treatments are inevitably countered through an adaptive process that fosters therapy resistance. Malignant cells achieve drug resistance through intrinsic and acquired mechanisms, rooted in genetic and non-genetic determinants. In particular, recent work has highlighted the role of intrinsic cellular heterogeneity in the emergence of transient drug-tolerant persister cells that survive drug treatment, as well as non-genetically driven cell plasticity toward stable resistance. However, these models do not account for the role of dose and treatment duration as extrinsic forces in eliciting cancer cell adaptation. Here, we show that these two components together drive the resistance of ovarian cancer cells to targeted therapy along a trajectory of cellular adaptation, that we denote the ‘resistance continuum’. We report that gradual dose exposure and prolonged treatment promote a continuous increase in fitness, and show that this process is mediated by evolving transcriptional, epigenetic and genetic changes that promote multiple cell state transitions. The resistance continuum is underpinned by the assembly of gene expression programs and epigenetically reinforced stress response regulation. Using both in vivo and in vitro models, we found that this process involves widespread reprogramming of cell survival pathways, including interferon response, lineage reprogramming, metabolic rewiring and oxidative stress regulation. Together, the resistance continuum reveals the dynamic nature of cellular adaptation, and carries implications for cancer therapies, as initial exposure to lower doses primes cells over time for increased resistance to higher doses. Beyond cancer, such continuous adaptation exposes a basic aspect of cellular plasticity, which may also be deployed in other biological systems such as development, immune response and host-pathogen interactions.
- Published
- 2022
32. Overriding Adaptive Resistance to Sorafenib Through Combination Therapy With Src Homology 2 Domain–Containing Phosphatase 2 Blockade in Hepatocellular Carcinoma
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Irene Oi-Lin Ng, Eunice Yuen Ting Lau, Stephanie Ma, Jin Ding, Terence Kin Wah Lee, Man Tong, Kwan Ho Tang, Carmen Oi Ning Leung, Noélia Che, Lena Zhou, and Katherine Po Sin Chung
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Sorafenib ,Carcinoma, Hepatocellular ,SH2 Domain-Containing Protein Tyrosine Phosphatases ,Antineoplastic Agents ,Receptor tyrosine kinase ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,Cell Line, Tumor ,medicine ,Humans ,Epidermal growth factor receptor ,neoplasms ,Protein kinase B ,Hepatology ,biology ,Chemistry ,Liver Neoplasms ,Receptor Protein-Tyrosine Kinases ,EPH receptor A2 ,digestive system diseases ,Drug Combinations ,Pyrimidines ,Editorial ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,biology.protein ,030211 gastroenterology & hepatology ,Signal transduction ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Background and aims The survival benefit of sorafenib for patients with hepatocellular carcinoma (HCC) is unsatisfactory due to the development of adaptive resistance. Increasing evidence has demonstrated that drug resistance can be acquired by cancer cells by activating a number of signaling pathways through receptor tyrosine kinases (RTKs); nevertheless, the detailed mechanism for the activation of these alternative pathways is not fully understood. Approach and results Given the physiological role of Src homology 2 domain-containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation of various signaling cascades, we first found that SHP2 was markedly up-regulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts. Upon sorafenib treatment, adaptive resistance was acquired in HCC cells through activation of RTKs including AXL, epidermal growth factor receptor, EPH receptor A2, and insulin-like growth factor 1 receptor, leading to RAS/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and AKT reactivation. We found that the SHP2 inhibitor SHP099 abrogated sorafenib resistance in HCC cell lines and organoid culture in vitro by blocking this negative feedback mechanism. Interestingly, this sensitization effect was also mediated by induction of cellular senescence. SHP099 in combination with sorafenib was highly efficacious in the treatment of xenografts and genetically engineered models of HCC. Conclusions SHP2 blockade by SHP099 in combination with sorafenib attenuated the adaptive resistance to sorafenib by impeding RTK-induced reactivation of the MEK/ERK and AKT signaling pathways. SHP099 in combination with sorafenib may be a safe therapeutic strategy against HCC.
- Published
- 2020
33. Targeting
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Han, Han, Shuai, Li, Ting, Chen, Michael, Fitzgerald, Shengwu, Liu, Chengwei, Peng, Kwan Ho, Tang, Shougen, Cao, Johara, Chouitar, Jiansheng, Wu, David, Peng, Jiehui, Deng, Zhendong, Gao, Theresa E, Baker, Fei, Li, Hua, Zhang, Yuanwang, Pan, Hailin, Ding, Hai, Hu, Val, Pyon, Cassandra, Thakurdin, Eleni, Papadopoulos, Sittinon, Tang, Francois, Gonzalvez, Haiquan, Chen, Victor M, Rivera, Rachael, Brake, Sylvie, Vincent, and Kwok-Kin, Wong
- Subjects
Lung Neoplasms ,Receptor, ErbB-2 ,Adenocarcinoma of Lung ,Apoptosis ,Exons ,Mice, SCID ,Ado-Trastuzumab Emtansine ,Xenograft Model Antitumor Assays ,Article ,Gene Expression Regulation, Neoplastic ,Mice ,INDEL Mutation ,Mice, Inbred NOD ,Antibodies, Bispecific ,Antineoplastic Combined Chemotherapy Protocols ,Tumor Cells, Cultured ,Animals ,Humans ,Female ,skin and connective tissue diseases ,Cell Proliferation - Abstract
No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC(50) of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC(50) / WT EGFR IC(50) ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20(YVMA) allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20(G776>VC) lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20(YVMA) tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20(YVMA) tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4(+) T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20(YVMA) insertion-mutant lung adenocarcinoma patients.
- Published
- 2021
34. Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC
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Kwan Ho Tang, Dean Y. Maeda, Argus Athanas, Carmine Fedele, Yuan Hao, John A Zebala, Han Han, Kwok-Kin Wong, Ting Chen, Kayla Guidry, James G. Christensen, Benjamin G. Neel, Alireza Khodadadi-Jamayran, Peter D. Olson, Jayu Jen, and Shuai Li
- Subjects
MAPK/ERK pathway ,Tumor microenvironment ,Chemistry ,Effector ,medicine ,Cancer research ,Cytotoxic T cell ,KRAS ,CXC chemokine receptors ,medicine.disease_cause ,Receptor ,CD8 - Abstract
Clinical trials of SHP2 inhibitors (SHP2i) alone and in various combinations are ongoing for multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras-and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.Statement of SignificanceOur study shows that inhibiting the SHP2/RAS/ERK pathway triggers NF-kB-dependent up-regulation of CXCR2 ligands and recruitment of S100A8high gMDSCs, which suppress T cells in NSCLC. Combining SHP2 and CXCR2 inhibitors blocks this gMDSC immigration, resulting in enhanced Th1 polarization, induction of CD8+ KLRG1+ effector T cells with high cytotoxic activity and improved survival in multiple NSCLC models.
- Published
- 2021
35. SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
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Benjamin G. Neel, Mitchell J. Geer, Kwok-Kin Wong, Brian Diskin, Takamitsu Hattori, Paolo Mita, Kai Wen Teng, Connor Foster, Joshua Leinwand, Carmine Fedele, Akiko Koide, Ting Chen, Wei Wang, Shohei Koide, Shuai Li, Kwan Ho Tang, Yubao Wang, David H. Peng, Jiehui Deng, Hao Ran, Igor Dolgalev, George Miller, and Ugur Ozerdem
- Subjects
0301 basic medicine ,Lung Neoplasms ,Myeloid ,endocrine system diseases ,Immunology ,Mutation, Missense ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,medicine.disease_cause ,Article ,law.invention ,Proto-Oncogene Proteins p21(ras) ,Mice ,03 medical and health sciences ,0302 clinical medicine ,law ,Carcinoma, Non-Small-Cell Lung ,Tumor Microenvironment ,medicine ,Animals ,Immunology and Allergy ,Enzyme Inhibitors ,Solid Tumors ,Mice, Knockout ,Tumor microenvironment ,Oncogene ,Chemistry ,Cancer ,medicine.disease ,digestive system diseases ,In vitro ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,Amino Acid Substitution ,030220 oncology & carcinogenesis ,Tumor immunology ,Cancer research ,Suppressor ,KRAS ,CD8 ,Carcinoma, Pancreatic Ductal - Abstract
G12C inhibitors (G12C-Is) have significant but limited efficacy in KRAS-mutant malignancies, mostly due to “adaptive resistance.” Combining SHP2 inhibitor (SHP2-I) with G12C-I abrogates adaptive resistance; evokes beneficial, tumor-specific changes in the immune microenvironment; and potentiates PD-1 blockade. SHP2-I also has direct, context-dependent effects on tumor vasculature., KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site–specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
- Published
- 2020
36. Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer
- Author
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Chewei Anderson Chang, Jayu Jen, Shaowen Jiang, Azin Sayad, Arvind Singh Mer, Kevin R. Brown, Allison M.L. Nixon, Avantika Dhabaria, Kwan Ho Tang, David Venet, Christos Sotiriou, Jiehui Deng, Kwok-kin Wong, Sylvia Adams, Peter Meyn, Adriana Heguy, Jane A. Skok, Aristotelis Tsirigos, Beatrix Ueberheide, Jason Moffat, Abhyudai Singh, Benjamin Haibe-Kains, Alireza Khodadadi-Jamayran, and Benjamin G. Neel
- Subjects
Receptor, ErbB-2 ,Breast Neoplasms ,mTORC1 ,Biology ,Lapatinib ,Article ,Metastasis ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,0303 health sciences ,Cancer ,medicine.disease ,respiratory tract diseases ,3. Good health ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,Signal Transduction ,medicine.drug - Abstract
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. “Drug-tolerant persisters” (DTP), a subpopulation of cancer cells that survive via reversible, nongenetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKI) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single-cell RNA sequencing reveals that HER2+ breast cancer cells cycle stochastically through a “pre-DTP” state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting shows that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor–dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation. Significance: DTPs are implicated in resistance to anticancer therapies, but their ontogeny and vulnerabilities remain unclear. We find that HER2 TKI-DTPs emerge from stochastically arising primed cells (“pre-DTPs”) that engage either of two distinct transcriptional programs upon TKI exposure. Our results provide new insights into DTP ontogeny and potential therapeutic vulnerabilities. This article is highlighted in the In This Issue feature, p. 873
- Published
- 2020
37. Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21
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Laurie Ailles, Christina Karamboulas, Victor W.H. Ho, Jalna Meens, Ali Hussain, Stephanie Poon, Gary D. Bader, Benjamin G. Neel, Veronique Voisin, Blaise A. Clarke, Julia Dmytryshyn, Joshua Paterson, Marcus Q. Bernardini, Kwan Ho Tang, and Ngoc Hoang Bao Bui
- Subjects
0301 basic medicine ,endocrine system diseases ,Immunology ,Cell ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cancer-Associated Fibroblasts ,Fibroblast activation protein, alpha ,Cell Line, Tumor ,Basic Helix-Loop-Helix Transcription Factors ,Tumor Microenvironment ,medicine ,Humans ,Immunology and Allergy ,Neoplasm Invasiveness ,Solid Tumors ,Transcription factor ,Cell Proliferation ,Ovarian Neoplasms ,Tumor microenvironment ,Cell growth ,Cancer ,medicine.disease ,female genital diseases and pregnancy complications ,Neoplasm Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,Ovarian cancer - Abstract
In this study, Hussain et al. demonstrate that cancer-associated fibroblasts (CAFs) in high-grade serous ovarian cancer are heterogeneous, that CAF state drives cancer aggressiveness and patient outcomes, and that TCF21 is a master regulator of CAF state., Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF “state.” Here, we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), coexist within the CD49e+ CAF compartment in high-grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes and that this is mediated by the ability of FAP-high, but not FAP-low, CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FAP-low–specific transcription factor TCF21 in FAP-high CAFs decreases their ability to promote invasion, chemoresistance, and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies.
- Published
- 2020
38. MA11.02 Targeting HER2 Exon 20–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor, Mobocertinib
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Hao Chen, Zhendong Gao, Hailin Ding, Jiansheng Wu, Yuanwang Pan, Michael Fitzgerald, Sittinon Tang, Kwan Ho Tang, Cassandra Thakurdin, Sylvie Vincent, Rachael L. Brake, Kwok K. Wong, Ting Chen, S. Cao, Val Pyon, C. Peng, Jiehui Deng, Victor M. Rivera, Theresa E. Baker, Fei Li, Hai Hu, Francois Gonzalvez, David H. Peng, Simin Liu, Shihua Li, Eleni Papadopoulos, Johara Chouitar, Han Han, and Hua Zhang
- Subjects
Pulmonary and Respiratory Medicine ,Lung ,business.industry ,medicine.drug_class ,Mutant ,medicine.disease ,Tyrosine-kinase inhibitor ,Exon ,medicine.anatomical_structure ,Oncology ,medicine ,Cancer research ,Adenocarcinoma ,business - Published
- 2021
39. OA12.03 Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC
- Author
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Kayla Guidry, D. Maeda, Kwan Ho Tang, Jayu Jen, Ting Chen, James G. Christensen, Benjamin G. Neel, Han Han, Peter D. Olson, Alireza Khodadadi-Jamayran, Argus Athanas, Kwok K. Wong, John A Zebala, Yuan Hao, Shihua Li, and Carmine Fedele
- Subjects
Pulmonary and Respiratory Medicine ,Antitumor activity ,Oncology ,business.industry ,Cancer research ,Medicine ,business ,T cell response - Published
- 2021
40. Molecular and functional heterogeneity of cancer associated fibroblasts in high-grade serous ovarian cancer
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Ali Hussain, Blaise A. Clarke, Marcus Q. Bernardini, Julia Dmytryshyn, Jalna Meens, Joshua Paterson, Laurie Ailles, Kwan Ho Tang, Benjamin G. Neel, Victor W.H. Ho, Stephanie Poon, Veronique Voisin, and Gary D. Bader
- Subjects
0301 basic medicine ,business.industry ,Cell ,Cancer ,medicine.disease ,03 medical and health sciences ,Serous fluid ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Fibroblast activation protein, alpha ,In vivo ,030220 oncology & carcinogenesis ,Cancer cell ,medicine ,Cancer research ,Serous ovarian cancer ,business ,Transcription factor - Abstract
Recent studies indicate that cancer-associated fibroblasts (CAFs) are phenotypically and functionally heterogeneous. However, little is known about CAF subtypes, the roles they play in cancer progression, and molecular mediators of the CAF “state”. Here we identify a novel cell surface pan-CAF marker, CD49e, and demonstrate that two distinct CAF states, distinguished by expression of fibroblast activation protein (FAP), co-exist within the CD49e+ CAF compartment in high grade serous ovarian cancers. We show for the first time that CAF state influences patient outcomes, and that this is mediated by the ability FAP-high (FH) but not FAP-low (FL) CAFs to aggressively promote proliferation, invasion and therapy resistance of cancer cells. Overexpression of the FL-specific transcription factor TCF21 in FH CAFs decreases their ability to promote invasion, chemoresistance and in vivo tumor growth, indicating that it acts as a master regulator of the CAF state. Understanding CAF states in more detail could lead to better patient stratification and novel therapeutic strategies. One sentence summary In this study we demonstrate that cancer-associated fibroblasts (CAFs) in high-grade serous ovarian cancer are heterogeneous, that CAF state drives cancer aggressiveness and patient outcomes, and that TCF21 is a master regulator of CAF state.
- Published
- 2019
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41. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer
- Author
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Gillian G. Baptiste, Belen Sundberg, Mirhee Kim, Joshua Leinwand, Zennur Sekendiz, Juan A. Kochen Rossi, Ruben D. Salas, Emma Kurz, Gregor Werba, Sorin A. A. Shadaloey, George Miller, Ruonan Chen, Berk Aykut, Shanmugapriya Selvaraj, Kwan Ho Tang, Miguel Liria, Emma Kruger, Susanna Nguy, Carmine Fedele, Salma Adam, Eric Li, Jason Karlen, Gustavo Sanchez, Dongling Wu, Chandan Buttar, Kwok-Kin Wong, Brian Diskin, Ting Chen, Wei Wang, Mautin Hundeyin, Junjie Wang, Cynthia Loomis, Muhammad Israr Ul Haq, Mohammad Saad Farooq, and Marcelo F. Cassini
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,Male ,medicine.medical_treatment ,T cell ,Immunology ,Programmed Cell Death 1 Receptor ,CD8-Positive T-Lymphocytes ,medicine.disease_cause ,B7-H1 Antigen ,03 medical and health sciences ,Interferon-gamma ,Mice ,0302 clinical medicine ,Cancer immunotherapy ,PD-L1 ,Cell Line, Tumor ,medicine ,Immune Tolerance ,Tumor Microenvironment ,Immunology and Allergy ,Animals ,Humans ,biology ,Chemistry ,Effector ,Macrophages ,Cell Differentiation ,Tumor antigen ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Self Tolerance ,Cell culture ,biology.protein ,Female ,Carcinogenesis ,CD8 ,030215 immunology ,Signal Transduction - Abstract
Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.
- Published
- 2019
42. SHP2 Inhibition Abrogates MEK inhibitor Resistance in Multiple Cancer Models
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Benjamin G. Neel, Carmine Fedele, Hao Ran, Kiyomi Araki, Jayu Jen, Wei Wei, Kwan Ho Tang, Diane M. Simeone, George Miller, and Brian Diskin
- Subjects
MAPK/ERK pathway ,0303 health sciences ,Gene knockdown ,biology ,Chemistry ,MEK inhibitor ,Cancer ,medicine.disease ,In vitro ,Receptor tyrosine kinase ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,biology.protein ,Ovarian cancer ,Triple-negative breast cancer ,030304 developmental biology - Abstract
Adaptive resistance to MEK inhibitors (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs, and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEK-I inhibits proliferation of multiple cancer cells in vitro. PTPN11 knockdown/MEK-I had similar effects, while expressing SHP099-binding mutants conferred resistance, demonstrating that SHP099 was on-target. This combination was efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas cancer and ovarian cancer and in wild-type RAS-expressing triple negative breast cancer. Biochemical studies show that SHP099 impedes SOS/RAS/MEK/ERK1/2 reactivation in response to MEK-Is and blocks ERK1/2-dependent transcriptional programs. SHP099 alone also inhibited RAS activation in some, but not all, KRAS-mutant lines. Hence, SHP099/MEK-I combinations could have therapeutic utility in multiple malignancies.
- Published
- 2018
43. SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
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Benjamin G. Neel, Mitchell J. Geer, Diane M. Simeone, Kwan Ho Tang, Wei Wei, George Miller, Jayu Jen, Ugur Ozerdem, Carmine Fedele, Hao Ran, Kiyomi Araki, and Brian Diskin
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Biology ,medicine.disease_cause ,Article ,Receptor tyrosine kinase ,03 medical and health sciences ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Trametinib ,Mitogen-Activated Protein Kinase Kinases ,Gene knockdown ,MEK inhibitor ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Oncology ,biology.protein ,Cancer research ,KRAS - Abstract
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding–defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies. Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237–49. ©2018 AACR. See related commentary by Torres-Ayuso and Brognard, p. 1210. This article is highlighted in the In This Issue feature, p. 1195
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- 2018
44. Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma
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Irene Oi-Lin Ng, Vincent Chi Ho Cheung, Terence Kin Wah Lee, Ping Lu, Stephanie Ma, Man Tong, Eunice Yuen Ting Lau, Kwan Ho Tang, and Jessica Lo
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Male ,Carcinoma, Hepatocellular ,Population ,Mice, Nude ,CD47 Antigen ,Tumor initiation ,Biology ,Morpholinos ,Metastasis ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Receptor, PAR-2 ,Progenitor cell ,education ,Protease-activated receptor 2 ,Cell Line, Transformed ,Cathepsin S ,Mice, Inbred BALB C ,education.field_of_study ,Antibiotics, Antineoplastic ,Hepatology ,CD47 ,Liver Neoplasms ,Cancer ,Genetic Therapy ,Middle Aged ,medicine.disease ,Cathepsins ,Xenograft Model Antitumor Assays ,Doxorubicin ,Neoplastic Stem Cells ,Cancer research ,Female ,Signal Transduction - Abstract
Identification of therapeutic targets against tumor-initiating cells (TICs) is a priority in the development of new therapeutic paradigms against cancer. We enriched a TIC population capable of tumor initiation and self-renewal by serial passages of hepatospheres with chemotherapeutic agents. In chemoresistant hepatospheres, CD47 was found to be up-regulated, when compared with differentiated progenies. CD47 is preferentially expressed in liver TICs, which contributed to tumor initiation, self-renewal, and metastasis and significantly affected patients' clinical outcome. Knockdown of CD47 suppressed stem/progenitor cell characteristics. CD47+ hepatocellular carcinoma (HCC) cells preferentially secreted cathepsin S (CTSS), which regulates liver TICs through the CTSS/protease-activated receptor 2 (PAR2) loop. Suppression of CD47 by morpholino approach suppressed growth of HCC in vivo and exerted a chemosensitization effect through blockade of CTSS/PAR2 signaling. Conclusion: These data suggest that CD47 may be an attractive therapeutic target for HCC therapy. (Hepatology 2014;60:179–191)
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- 2014
45. Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma
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Si Lok, KY Wong, Man Tong, Kwan Ho Tang, Xin Yuan Guan, Stephanie Ma, Kwok Wah Chan, Pak Shing Kwan, Jessie Y.J. Bao, Jin Na Chen, Li Fu, and Yan Ru Qin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,Tumor suppressor gene ,MAP Kinase Signaling System ,Molecular Sequence Data ,Down-Regulation ,Mice, Nude ,Endocytic recycling ,Transcriptome ,Mice ,Downregulation and upregulation ,Cell Movement ,Cell Line, Tumor ,Internal medicine ,Carcinoma ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,Neoplasm Invasiveness ,Promoter Regions, Genetic ,neoplasms ,Base Sequence ,Neovascularization, Pathologic ,business.industry ,Gene Expression Profiling ,DNA Methylation ,Esophageal cancer ,medicine.disease ,digestive system diseases ,Gene expression profiling ,rab GTP-Binding Proteins ,DNA methylation ,Carcinoma, Squamous Cell ,Cancer research ,business - Abstract
Esophageal squamous cell carcinoma (ESCC), the major histologic subtype of esophageal cancer, is a devastating disease characterized by distinctly high incidences and mortality rates. However, there remains limited understanding of molecular events leading to development and progression of the disease, which are of paramount importance to defining biomarkers for diagnosis, prognosis, and personalized treatment. By high-throughout transcriptome sequence profiling of nontumor and ESCC clinical samples, we identified a subset of significantly differentially expressed genes involved in integrin signaling. The Rab25 gene implicated in endocytic recycling of integrins was the only gene in this group significantly downregulated, and its downregulation was confirmed as a frequent event in a second larger cohort of ESCC tumor specimens by quantitative real-time PCR and immunohistochemical analyses. Reduced expression of Rab25 correlated with decreased overall survival and was also documented in ESCC cell lines compared with pooled normal tissues. Demethylation treatment and bisulfite genomic sequencing analyses revealed that downregulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation. Functional studies using lentiviral-based overexpression and suppression systems lent direct support of Rab25 to function as an important tumor suppressor with both anti-invasive and -angiogenic abilities, through a deregulated FAK–Raf–MEK1/2–ERK signaling pathway. Further characterization of Rab25 may provide a prognostic biomarker for ESCC outcome prediction and a novel therapeutic target in ESCC treatment. Cancer Res; 72(22); 6024–35. ©2012 AACR.
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- 2012
46. CD24+ Liver Tumor-Initiating Cells Drive Self-Renewal and Tumor Initiation through STAT3-Mediated NANOG Regulation
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Vincent Chi Ho Cheung, Terence Kin Wah Lee, Kwan Ho Tang, Antonia Castilho, Stephanie Ma, and Irene Oi-Lin Ng
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Homeobox protein NANOG ,Adult ,STAT3 Transcription Factor ,Liver tumor ,Carcinoma, Hepatocellular ,Cellular differentiation ,Population ,Tumor initiation ,Biology ,Metastasis ,Mice ,Cell Line, Tumor ,medicine ,Genetics ,Animals ,Humans ,Neoplasm Metastasis ,Phosphorylation ,education ,skin and connective tissue diseases ,Aged ,Cell Proliferation ,Cisplatin ,Aged, 80 and over ,Homeodomain Proteins ,education.field_of_study ,CD24 ,Liver Neoplasms ,CD24 Antigen ,Cell Differentiation ,Nanog Homeobox Protein ,Cell Biology ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Gene Knockdown Techniques ,Immunology ,Cancer research ,Neoplastic Stem Cells ,Molecular Medicine ,medicine.drug - Abstract
Summary Tumor-initiating cells (T-ICs) are a subpopulation of chemoresistant tumor cells that have been shown to cause tumor recurrence upon chemotherapy. Identification of T-ICs and their related pathways are therefore priorities for the development of new therapeutic paradigms. We established chemoresistant hepatocellular carcinoma (HCC) xenograft tumors in immunocompromised mice in which an enriched T-IC population was capable of tumor initiation and self-renewal. With this model, we found CD24 to be upregulated in residual chemoresistant tumors when compared with bulk tumor upon cisplatin treatment. CD24 + HCC cells were found to be critical for the maintenance, self-renewal, differentiation, and metastasis of tumors and to significantly impact patients' clinical outcome. With a lentiviral-based knockdown approach, CD24 was found to be a functional liver T-IC marker that drives T-IC genesis through STAT3-mediated NANOG regulation. Our findings point to a CD24 cascade in liver T-ICs that may provide an attractive therapeutic target for HCC patients.
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- 2011
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47. miR-130b Promotes CD133+ Liver Tumor-Initiating Cell Growth and Self-Renewal via Tumor Protein 53-Induced Nuclear Protein 1
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Paul B.S. Lai, Kwan Ho Tang, Antonia Castilho, Ka Fai To, Nathalie Wong, Stephanie Ma, Pak Shing Kwan, Xin Yuan Guan, Kwok Wah Chan, Irene Ng, Terence K. Lee, Kwan Man, Bo-Jian Zheng, Yuen Piu Chan, and Chung Mau Lo
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Adult ,Male ,Carcinoma, Hepatocellular ,Liver tumor ,Mice, SCID ,Biology ,Mice ,Antigen ,Antigens, CD ,Cancer stem cell ,Cell Line, Tumor ,microRNA ,Genetics ,medicine ,Animals ,Humans ,Gene silencing ,AC133 Antigen ,neoplasms ,Heat-Shock Proteins ,Aged ,Cell Proliferation ,Glycoproteins ,Aged, 80 and over ,Cell growth ,Liver Neoplasms ,Nuclear Proteins ,Cell Biology ,Middle Aged ,medicine.disease ,In vitro ,carbohydrates (lipids) ,MicroRNAs ,Liver ,Cell culture ,embryonic structures ,Immunology ,Neoplastic Stem Cells ,Cancer research ,Molecular Medicine ,Female ,Carrier Proteins ,Peptides - Abstract
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133⁻ counterparts, CD133(+) cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133(+) cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133(+) tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133(+) and CD133⁻ cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133(+) TICs. Functional studies on miR-130b lentiviral-transduced CD133⁻ cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133(+) TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133⁻ cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133(+) liver TICs, in part, via silencing TP53INP1.
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- 2010
48. Abstract LB-338: SHP2 inhibition enhances sensitivity to MEK inhibitors in multiple resistant cancer models
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Wei Wei, George Miller, Brian Diskin, Benjamin G. Neel, Carmine Fedele, Hao Ran, and Kwan Ho Tang
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MAPK/ERK pathway ,Cancer Research ,Kinase ,Cancer ,Biology ,medicine.disease_cause ,medicine.disease ,Receptor tyrosine kinase ,Cell killing ,Oncology ,Cancer cell ,Cancer research ,medicine ,biology.protein ,KRAS ,Triple-negative breast cancer - Abstract
Targeting tumors with kinase inhibitors induces complex adaptive programs that enable the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. Most tumors developing resistance to MEK inhibitors upregulate and/or activation of at least one of several different receptor tyrosine kinases (RTKs), which drive resistance. Notably, different RTKs or RTK combinations are upregulated in different cancer cells, even those from the same histotype. SHP2 (encoded by PTPN11) is required for RAS/ERK pathway activation downstream of most RTKs, suggesting that it might provide a common targetable resistance node in multiple resistant cancer cell lines. We show that the addition of a newly identified SHP2 inhibitor, SHP099, to MEK therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cancer models in vitro and in vivo. These effects occurred in a wide range of malignancies, including KRAS mutant pancreas, lung cancer, triple negative breast cancer, and serous ovarian cancer cell lines, as well as in PDX and GEMM models. SHP099 effects were overcome by expressing an SHP2 mutant that loses drug binding but retain catalytic activity and regulation, demonstrating that on target effects of the inhibitor. Mechanistic studies across multiple cellular cancer models suggest that SHP2 inhibition by SHP099 prevents the compensatory RAS and ERK1/2 reactivation in response to MEK therapy and impedes the engagement of the ERK1/2 transcriptional programs (i.e., MYC, ETV1, FOSL1, etc.) and signaling outputs that characterize the drug-tolerant state. Combining full doses of MEK inhibitors and SHP099 causes significant toxicity in mice, but non-toxic, efficacious dosing regimens can be achieved. Our findings suggest that SHP099, in combination with MEK inhibition is a promising therapeutic strategy for enhancing the effectiveness of targeted therapies. Citation Format: Carmine Fedele, Kwan Ho Tang, Hao Ran, Wei Wei, Brian Diskin, George Miller, Benjamin G. Neel. SHP2 inhibition enhances sensitivity to MEK inhibitors in multiple resistant cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-338.
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- 2018
49. Prostate cancer cells modulate osteoblast mineralisation and osteoclast differentiation through Id-1
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Xianghong Wang, Yung-Tuen Chiu, Yuen-Piu Chan, Yong-Chuan Wong, Chua Cw, Hiu-Fung Yuen, Kwan Ho Tang, Mohamed El-Tanani, Kwok Wah Chan, Cian M. McCrudden, and Ka Kui Chan
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Inhibitor of Differentiation Protein 1 ,Male ,Cancer Research ,medicine.medical_specialty ,Cellular differentiation ,Osteoclasts ,Prostate cancer ,Calcification, Physiologic ,Osteoclast ,Prostate ,Osteogenesis ,Internal medicine ,Cell Line, Tumor ,LNCaP ,medicine ,Humans ,Neoplasm Metastasis ,Id-1 ,bone metastasis ,Osteoblasts ,business.industry ,Cancer ,Bone metastasis ,Prostatic Neoplasms ,Osteoblast ,Cell Differentiation ,medicine.disease ,prostate cancer ,Endocrinology ,medicine.anatomical_structure ,Oncology ,osteoclast ,Cancer research ,osteoblast ,business ,Translational Therapeutics - Abstract
Background: Id-1 is overexpressed in and correlated with metastatic potential of prostate cancer. The role of Id-1 in this metastatic process was further analysed. Methods: Conditioned media from prostate cancer cells, expressing various levels of Id-1, were used to stimulate pre-osteoclast differentiation and osteoblast mineralisation. Downstream effectors of Id-1 were identified. Expressions of Id-1 and its downstream effectors in prostate cancers were studied using immunohistochemistry in a prostate cancer patient cohort (N=110). Results: We found that conditioned media from LNCaP prostate cancer cells overexpressing Id-1 had a higher ability to drive osteoclast differentiation and a lower ability to stimulate osteoblast mineralisation than control, whereas conditioned media from PC3 prostate cancer cells with Id-1 knockdown were less able to stimulate osteoclast differentiation. Id-1 was found to negatively regulate TNF-β and this correlation was confirmed in human prostate cancer specimens (P=0.03). Furthermore, addition of recombinant TNF-β to LNCaP Id-1 cell-derived media blocked the effect of Id-1 overexpression on osteoblast mineralisation. Conclusion: In prostate cancer cells, the ability of Id-1 to modulate bone cell differentiation favouring metastatic bone disease is partially mediated by TNF-β, and Id-1 could be a potential therapeutic target for prostate cancer to bone metastasis.
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- 2009
50. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling
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Irene Oi-Lin Ng, Carol Man Tong, Pak Shing Kwan, Paul B.S. Lai, Yuen Piu Chan, Ka Fai To, Kwan Man, Stephanie Ma, Kwok Wah Chan, Terence K. Lee, Chung Mau Lo, Kwan Ho Tang, and Xin Yuan Guan
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MAPK/ERK pathway ,Liver tumor ,Carcinoma, Hepatocellular ,Angiogenesis ,Chemokine CXCL1 ,Population ,Mice, Nude ,Biology ,medicine.disease_cause ,Mice ,Antigens, CD ,Cell Line, Tumor ,medicine ,Animals ,Hepatectomy ,Humans ,Interleukin 8 ,AC133 Antigen ,education ,Cells, Cultured ,Neurotensin ,Cell Proliferation ,Glycoproteins ,Feedback, Physiological ,Mitogen-Activated Protein Kinase Kinases ,education.field_of_study ,Hepatology ,Neovascularization, Pathologic ,Cell growth ,Interleukin-8 ,Liver Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,CXCL1 ,Liver ,Cancer research ,Neoplastic Stem Cells ,Carcinogenesis ,Peptides ,Signal Transduction - Abstract
A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133+ liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133+ cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133+ liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133+ liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133+ liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133+ liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. Conclusion: CD133+ liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade. (Hepatology 2012)
- Published
- 2011
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