Lluís Morey

University of Miami

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Ramin Shiekhattar

Sylvester Comprehensive Cancer Center

Luisa Cimmino

Sylvester Comprehensive Cancer Center

Aymee Perez

Sylvester Comprehensive Cancer Center

Terrence Bradley

University of Miami

Yvonne Dinh

IQVIA (United States)

Amber Thomassen

Sylvester Comprehensive Cancer Center

Arthur Zelent

Institute of Cancer Research

Mina M. Tayari

University of Miami

Justin M. Watts

Sylvester Comprehensive Cancer Center

Helena G. Dos Santos

Centro Hospitalar de Vila Nova de Gaia

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University of Miami

116

Sylvester Comprehensive Cancer Center

105

University of Cambridge

Pompeu Fabra University

Centre for Genomic Regulation

Memorial Sloan Kettering Cancer Center

Hospital del Mar Research Institute

Université Libre de Bruxelles

Hospital Del Mar

Institut Jules Bordet

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C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer

Nature Communications (2024)

Seyedeh Fatemeh Razavipour Hyunho Yoon Kibeom Jang Minsoon Kim Hend M. Nawara

Abstract In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC , the Notch ligand JAG1 , and ANGPTL4 . p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12 . Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene profile is over-represented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues.

10.1038/s41467-024-48742-y

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Supplementary Legend from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

Supplementary Legend

Legend

10.1158/1078-0432.22481372.v1

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Table S4 from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

Table S4

Table (database)

10.1158/1078-0432.22481360.v1

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Table S5 from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

Table S5

Table (database)

10.1158/1078-0432.22481357.v1

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Abstract 653: Tumor cell-macrophage crosstalk drives immune suppression in pancreatic cancer

Cancer Research (2023)

Siddharth Mehra Vanessa T. Garrido Samara P. Singh Iago De Castro Silva Zhiqun Zhou

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) due to its unique genetic makeup and immunosuppressive tumor microenvironment (TME) produce a lack of response to current therapies. Macrophages, constitute a large innate immune subset and play a vital role in establishing an immune-suppressive microenvironment. Previously, we have identified Cyclic AMP Response Element Binding protein 1 (CREB) as a tumor cell-intrinsic oncogenic factor that promotes disease aggressiveness, poor survival, and immune suppression. Based on these, we sought to determine CREB mediated mechanisms of tumor-macrophage cross talk in driving immunosuppressive phenotype in PDAC. Methods: We have generated a genetically engineered mouse model (GEMM) of pancreas-specific CREB deletion (CREBfl/fl) in LSL-KrasG12D/+; Trp53 R172H/+; Pdx1Cre/+ (KPC) mice. CRISPR/CAS9-based genomic editing was utilized to ablate CREB (CREBKO) in KPC tumor cells. RNA-sequencing analysis was performed in KPC CREBKO tumor cells. ChIP-qPCR analysis was performed in KPC tumor cells. Orthotopic tumor implantation of these cells was performed in the pancreata of mice. Immunophenotyping was accomplished to assess changes in the immune subsets with CREB deletion in vivo. Additionally, these tissues were also processed for single-cell RNA (scRNA) transcriptomics analysis to evaluate the impact of CREB deletion on different cellular constituents within the TME. Results: CREB deletion in the KPC GEMM led to a significant reduction in the primary tumor burden, liver metastases, and improved overall survival compared to wild-type KPC. In assessing the immune repercussions of CREB deletion, we observed a decreased infiltration of tumor-promoting CD11b+ F4/80+ CD206+ tumor-associated macrophages (TAMs) and a concomitant increase in the antigen-presenting M1-like macrophages (F4/80+MHC-IIhighCD86high). Additionally, scRNA sequencing analysis within the macrophage compartment in CREBKO tumors revealed significant enrichment of M1 hallmark signaling pathways. Further, CREB ablation in these tumors facilitated increased infiltration of activated effector memory CD8+ T cells and resulted in enhanced adaptive immune response. RNA transcriptomic-based analysis of CREBKO tumor cells revealed downregulation of Leukemia inhibitory factor (LIF) as of the top targets. Mechanistically, ChIP qPCR analysis after CREB1 pulldown confirmed its occupancy on LIF promoter region. Further, on exploring the role of CREB regulated LIF on immune subsets, incubation of macrophages with CREBWT conditioned media in the presence of LIF neutralizing antibody or blocking its receptor (LIFR) decreases polarization of macrophages towards M2 like phenotype. Conclusion: These findings broaden our understanding of the tumor cell-intrinsic role of CREB in fostering immunosuppressive profile via LIF by promoting skewness of TAMs towards M2 like state in PDAC. Citation Format: Siddharth Mehra, Vanessa Garrido, Samara Singh, Iago De Castro Silva, Zhiqun Zhou, Supriya Srinivasan, Luis Alberto Nivelo, Anna Bianchi, Andrew Adams, Haleh Amirian, Lluis Morey, Ban Yuguang, Alejandro Villarino, Jashodeep Datta, Nipun Merchant, Nagaraj Nagathihalli. Tumor cell-macrophage crosstalk drives immune suppression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 653.

Tumor progression

10.1158/1538-7445.am2023-653

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3D structures of individual mammalian genomes studied by single-cell Hi-C

Nature (2017)

Tim J. Stevens David Lando Srinjan Basu Liam P. Atkinson Yang Cao

Folding (DSP implementation)

Chromosome conformation capture

10.1038/nature21429

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Table S6 from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

Table S6

10.1158/1078-0432.22481354

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Table S7 from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

Table S7

Table (database)

10.1158/1078-0432.22481351.v1

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Data from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

<div>AbstractPurpose:In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).Patients and Methods:Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).Results:ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid–target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.Conclusions:These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.</div>

Tretinoin

10.1158/1078-0432.c.6530669

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Figure S1 from Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies

Mina M. Tayari Helena G. Dos Santos Deukwoo Kwon Terrence Bradley Amber Thomassen

Supplementary Figure S1. Treatment-related adverse events (TRAEs) in patients treated with ATRA-TCP.

10.1158/1078-0432.22481387

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