bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C023: PTEN/STAT3 pathway in cancer-associated fibroblasts in Pancreatic Cancer
Authors: Saberi Samaneh , Bumbleburg Cameron , Jordan Victoria , Lefler Julia E. , Sharma Sudarshana , Ostrowski Michael C.
Published: January 2024

Pancreatic cancer is a devastating disease with a high mortality rate with a five-year survival rate of 12%. Recent studies have shed light on the crucial role of cancer-associated fibroblasts (CAFs) in shaping the tumor microenvironment. Our group demonstrated PTEN loss occurs in CAFs in ~25% of PDAC patient samples, which leads to increased activation of signaling pathways in CAFs, including the STAT3 pathway. Conditional deletion of STAT3 in CAFs in a dual flpO/cre recombinase PDAC model correlated with increased survival, decreased M2-like macrophages and increased T-cell infiltration. In the present study we aimed to test the hypothesis that direct interactions between PTEN and STAT3 in cancer CAFs contributes to an immuno-suppressive tumor microenvironment in pancreatic ductal carcinoma (PDAC). To address this hypothesis, we utilized CAFS isolated from the dual recombinase PDAC model. Proximity ligation assays with these CAFS demonstrated that PTEN-STAT3 are in a complex in the cell cytosol that translocate to the nucleus upon IL6 treatment. This finding was validated by co-immunoprecipitation experiments. ChIP-seq analysis of CAFs with PTEN and pSTAT3/STAT3 antibodies revealed a significant overlap in PTEN and pSTAT3/STAT3 occupation of gene promoters. Integrative analysis of PTEN-STAT3 bound genes with corresponding RNA-seq data revealed that the PTEN/STAT3 complex targets cytokines and ligands that directly affect T-cell function, contributing to an immune suppressive microenvironment. Analysis of human PDAC samples support the relationship between STAT3 activation and T-cell activity. Identifying PTEN/STAT3 targets in CAFs may provide new avenues for overcoming the anti-tumor immune responses in PDAC.

Citation Format: Samaneh Saberi, Cameron Bumbleburg, Victoria Jordan, Julia E. Lefler, Sudarshana Sharma, Michael C. Ostrowski. PTEN/STAT3 pathway in cancer-associated fibroblasts in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C023.
Abstract C024: Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer
Authors: Singh Rima , Yousefian Natalie , Steele Nina , Halbrook Christopher
Published: January 2024

Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer related deaths in the US. This mortality is strongly linked to the complex PDA tumor microenvironment that drives resistance to chemotherapy and immune suppression. Most patients succumb to metastatic disease, with liver being the most frequently colonized organ. Despite this, most pre-clinical studies have focused on primary PDA models to study the disease. Accordingly, the extent that the liver metastatic niche promotes immune evasion and resistance to treatment remains unclear. To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. To define the similarities and differences between cell types present in these tumors, we employed a single-cell transcriptomics approach. Our analysis has identified shared populations of malignant epithelial, stromal, and immune cells between lesions, allowing for a direct comparison of programming. Here, we have observed that the dominant populations of PDA cells in pancreas vs. liver tumors engage in distinct metabolic programs that suggest different actionable vulnerabilities. Beyond these, we also observed fibroblasts and myeloid sub-populations that are exclusive to liver tumors. These data further support our hypothesis that alternative mechanisms of metabolic, immune, and stromal interactions take place in the metastatic tumor microenvironment. To define these crosstalk networks, we employed the interactome tool CellChat, which has uncovered unique signaling interactions between the CAF and cancer cell populations in pancreatic and liver tumors. Overall, these data have the potential to lead to new avenues to directly target cancer cells or engage an effective immune response that can be designed to treat metastatic pancreatic cancer- an urgent clinical need.

Citation Format: Rima Singh, Natalie Yousefian, Nina Steele, Christopher Halbrook. Single-cell transcriptomics reveals unique stromal and metabolic heterogeneity in liver metastatic pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C024.
Abstract C032: The involvement of the splanchnic program at the cellular and molecular levels in pancreatic cancer associated fibroblasts
Authors: Walter Tom , Han Lu , Ostrowski Michael
Published: January 2024

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by a dense stroma primarily composed of cancer associated fibroblasts (CAFs). Our group recently performed a lineage tracing study using genetically engineered mouse models. This study demonstrated that CAFs and pancreatic tissue resident fibroblasts (TRFs) are both derived from the fetal splanchnic mesenchyme, an area of mesoderm next to the foregut endoderm. To determine whether two major subtypes of CAFs are derived from the splanchnic mesenchyme, I analyzed co-expression of the lineage tracing marker Tomato and CAF subtype marker a smooth muscle actin (aSMA). This suggests that both myofibroblasts (aSMA high) and inflammatory fibroblasts (aSMA low) are derived from the splanchnic mesenchyme. Furthermore, we found that transcription factor Gata6 is expressed in the splanchnic mesenchyme and in some CAFs. We constructed mouse genetic models where Gata6 is specifically deleted in fibroblasts. These Gata6 conditional knock out mice had increased tumor burden, suggesting that stromally-expressed Gata6 has a tumor restraining role. We derived CAF and TRF cell lines from these genetic mouse models and their littermate normal mice. My preliminary data suggest that several important fibroblast factors, including type I collagen, aSMA, and Interleukin 6, are upregulated in the Gata6 KO CAFs and TRFs relative to normal CAFs and TRFs. In summary, our study showed that two major subtypes of pancreatic CAFs are derived from the splanchnic mesenchyme, and splanchnic factors may play a role in adult pancreatic fibroblasts to regulate the expression of critical fibroblast genes.

Citation Format: Tom Walter, Lu Han, Michael Ostrowski. The involvement of the splanchnic program at the cellular and molecular levels in pancreatic cancer associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C032.
Abstract C036: Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers
Authors: Wang Yao , Apostolopoulou Hara , Sanyal Arjun , Sun Hong , Sieland Cynthia , Gupta Kavya , Ye Jiayu , Gibbs David , Wong Paul , Vasilis Ntranos , Huang Sui , Gardner James , Maker Ajay , Tlsty Thea , Bhushan Anil , Alliston Tamara
Published: January 2024

The stroma that surrounds the tumor in many solid cancers exhibits potent immunosuppressive activity to promote tumor progression and confer resistance to immune-based therapies. Cancer associated fibroblasts (CAFs) encompassing functionally distinct populations are key components of the stroma that are emerging as a key cell type in regulating an immune response. However, the mechanisms by which CAFs can directly suppress the immune activity to promote tumor growth is not clear. Here, we identify that a subset of CAF in both rodent and human stromagenic cancers that displays characteristics of senescent fibroblasts and referred to as sCAFs. We show that sCAFs secrete a decoy protein that interferes with cytotoxic activity of activated T effector (Teff) cells. In mouse models for stroma-rich pancreatic cancer, administration of an antibody that blocked the decoy protein resulted in recalibration of the stromal fibroblast by promoted the formation of interferon-licensed-fibroblast cells at the expense of sCAFs. This switch not only enhanced infiltration of tumor-infiltrating T cells but also alleviated their direct suppression resulting in enhanced effector function and tumor regression. Collectively, these results point to the potent immunosuppressive activity of sCAFs mediated by decoy protein as a mechanism by which stroma can promote tumor progression. As stromagenic-cancers are resistance to current therapies, the development of treatments involving blocking of decoy protein may inhibit tumor growth and improve patient survival.

Citation Format: Yao Wang, Hara Apostolopoulou, Arjun Sanyal, Hong Sun, Cynthia Sieland, Kavya Gupta, Jiayu Ye, David Gibbs, Paul Wong, Ntranos Vasilis, Sui Huang, James Gardner, Ajay Maker, Thea Tlsty, Anil Bhushan, Tamara Alliston. Restoration of T effector cells function by targeting senescent cancer-associated fibroblast in tumor microenvironment of stroma-rich cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C036.
Abstract C038: Interim pharmacodynamic analyses of mitazalimab in combination with FOLFIRINOX in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) identify CD4 effector T cells as a correlate of treatment outcomes
Authors: Wattenberg Max M. , Smith Karin Enell , de Coana Yago Pico , Jimenez David Gomez , Carlsson Malin , Ambarkhane Sumeet Vijay , Ellmark Peter , Beatty Gregory L.
Published: January 2024

CD40 agonists are being investigated in combination with standard of care chemotherapy as an approach to trigger anti-tumor immunity and improve outcomes for patients with cancer. Preclinical models suggest the importance of appropriate sequencing of chemotherapy and a CD40 agonist. Herein, we report interim pharmacodynamic analyses and their association with outcomes from a Phase 2 study evaluating mitazalimab, a CD40 agonist, in combination with modified (m) FOLFIRINOX chemotherapy as first line therapy in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients with newly diagnosed mPDAC were treated with mitazalimab on day 1 prior to beginning an every 2-week regimen on day 8 of mFOLFIRINOX followed by mitazalimab 48 hours later. Tumor response was determined by RECIST v1.1 imaging. Peripheral blood was analyzed for selected cytokines and chemokines and by flow cytometry to assess changes in leukocyte subsets including B cells, monocytes, T cells, and NK cells. The neutrophil-to-lymphocyte ratio was determined from complete blood counts. The analysis included 23 patients with associated response data and indicated a mitazalimab-specific contribution to tumor response. Mitazalimab triggered an expected immune response characterized by transient cytokine (IL-8, IP-10, MCP-1, and MIP1b) release and B cell depletion. Chemotherapy provoked a reduction in classical monocytes and proliferating CD4+ T cells. Both mitazalimab and chemotherapy caused a transient reduction in circulating dendritic cells and NK cells. Tumor response was associated with an expansion in the frequency of effector CD4 T cells (p < 0.0001) at day 8 after receiving mitazalimab but did not correlate with neutrophil-to-lymphocyte ratio (p = 0.851). In conclusion, mitazalimab and FOLFIRINOX modulate immune responses in patients with mPDAC in different ways. Interim results of pharmacological analyses identify CD4 effector T cells as a correlate of treatment outcomes suggesting the contribution of mitazalimab to tumor responses.

Citation Format: Max M. Wattenberg, Karin Enell Smith, Yago Pico de Coana, David Gomez Jimenez, Malin Carlsson, Sumeet Vijay Ambarkhane, Peter Ellmark, Gregory L. Beatty. Interim pharmacodynamic analyses of mitazalimab in combination with FOLFIRINOX in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) identify CD4 effector T cells as a correlate of treatment outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C038.
Abstract C039: Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma
Authors: Wen Hui-Ju , Crawford Howard
Published: January 2024

Activation of cellular signaling pathways by crosstalk between tumor cells and their microenvironment is an essential mechanism supporting pancreatic carcinogenesis. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. systemic inhibition of ADAM17 led to a reduction in tumor burden and a concomitant decrease in EGFR activation. These effects were observed exclusively in the immunocompetent animals, but not in the immunodeficient animals. It implicates that inhibition of tumor growth by MEDI3622 is highly dependent on the immune response. Furthermore, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells for tumor killing. Altogether, ADAM17 blockade displays a pronounced anti-tumor effect, suggesting ADAM17 as a therapeutic target of pancreatic cancer.

Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C039.
Abstract C044: Macropinocytic stress reprograms cancer-associated fibroblasts and enhances therapeutic responses in pancreatic cancer
Authors: Zhang Yijuan , Maganti Swetha , Hope Jennifer , Ling Li , Galapate Cheska Marie , Carrette Florent , Bradley Linda , Commisso Cosimo
Published: January 2024

Macropinocytosis is a fundamental metabolic pathway that has been demonstrated to support the survival and function of tumor cells and cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) through in vitro studies and xenograft mouse models. However, the impact of macropinocytosis on the PDAC tumor microenvironment in an immune-competent setting remains poorly understood. In this study, we utilized the selective inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) to block macropinocytosis in both tumor cells and CAFs in syngeneic PDAC mouse models. We observed that EIPA treatment inhibited PDAC tumor growth, which was accompanied by reduced tumor proliferation and increased cell apoptosis. Moreover, EIPA treatment decreased the presence of myofibroblastic CAFs and collagen deposition within PDAC tumors, while also promoting the expansion of tumor vasculature. By modifying the tumor stroma, EIPA priming enhanced drug delivery and improved the effectiveness of PDAC chemotherapy. Interestingly, immune profiling of PDAC tumors revealed that EIPA administration specifically increased the infiltration of CD8+ and CD4+ T cells. We discovered that EIPA induced changes in the cytokine/chemokine landscape within tumors by triggering an inflammatory CAF (iCAF)-like phenotype. Mechanistically, we discerned that inhibition of macropinocytosis triggers metabolic stress that in turn activates stress-responsive transcription factors and promotes the expression of early-phase proinflammatory cytokines and chemokines in mouse CAFs. Notably, combination treatment with EIPA and immune checkpoint blockade (ICB) reduced PDAC tumor burden and significantly inhibited tumor metastasis. Overall, our findings establish that macropinocytosis functions to support the barrier function of the stroma by maintaining fibroblastic identity and provide further evidence that inhibition of macropinocytosis represents a promising therapeutic modality in PDAC.

Citation Format: Yijuan Zhang, Swetha Maganti, Jennifer Hope, Li Ling, Cheska Marie Galapate, Florent Carrette, Linda Bradley, Cosimo Commisso. Macropinocytic stress reprograms cancer-associated fibroblasts and enhances therapeutic responses in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C044.
Abstract C059: Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer
Authors: Vyas Foram , Grünwald Barbara , Aliar Kazeera , Jang Gun Ho , O'Kane Grainne , Kislinger Thomas , Gallinger Steven , Haibe-Kains Benjamin , Khokha Rama
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) has a complex disease pathobiology and poor treatment options, emphasizing the need for novel therapeutic targets. Hub genes have high connectivity (i.e., exceptionally many interaction partners), for example, certain proteases with numerous interaction partners. Thereby, hub genes are often central biological regulators and dysregulated proteolysis is indeed a key trait of malignant tissues. Here, we aimed to identify novel protease-related hub genes with potential involvement in pancreatic cancer. We applied an integrative computational approach to compartment-specific multiOMIC profiles of laser-capture micro-dissected human PDAC tissues (n = 32) and queried associations of identified candidate genes with clinical outcomes in early (n = 186) and advanced PDAC patients (n = 253). This identified 20 protease-related genes with ≥ 10 physically verified interaction partners in pancreatic cancer. Among these, the pyrimidine biosynthesis regulator gene CAD emerged as a potentially druggable target in pancreatic cancer. CAD expression was nearly restricted to the malignant PDAC epithelium. Furthermore, higher CAD expression was associated with significantly worse overall survival in patients with advanced but not resectable disease, suggesting a role in treatment response rather than disease progression. Moreover, patients with higher CAD expression specifically demonstrated poor response to mFFX but not Gemcitabine-nab-Paclitaxel treatment, which is in line with previous reports on CAD expression being protective against 5-Fluouracil, a component of FFX. Moving forward, we will interrogate the role of CAD in PDAC tissue biology and scrutinize its involvement in FFX resistance, using patient-derived organoids.

Citation Format: Foram Vyas, Barbara Grünwald, Kazeera Aliar, Gun Ho Jang, Grainne O'Kane, Thomas Kislinger, Steven Gallinger, Benjamin Haibe-Kains, Rama Khokha. Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C059.
Abstract C060: Characterization of a collection of patient-derived xenograft models for pancreatic ductal adenocarcinoma translational research
Authors: Yáñez Mariana , Arenas Enrique Javier , Macarulla Teresa , Tian Tian , Arribas Joaquín , Llorente Sofía , Fabregat Carles , Escorihuela Marta , Castet Florian , Querol Jessica , Salcedo Maria Teresa
Published: January 2024

To conduct successful translational research for pancreatic ductal adenocarcinoma (PDAC), it is imperative to have preclinical models that accurately reflect the intricate molecular, genomic, and histological features of the disease. Patient-derived xenografts (PDXs) have emerged as invaluable platforms for studying tumor biology and personalized therapeutic intervention. Here we present a collection of 32 PDAC PDX models established and fully characterized in our institution. This PDAC PDX collection was generated with tissue from both primary and metastatic lesions, comprehensively representing the disease spectrum. Genomic profiling using next-generation sequencing revealed a remarkable concordance between the PDX samples and their original patient tumor tissue. Notably, identifying common driver mutations associated with PDAC further validates the clinical relevance of this PDX collection. Moreover, histopathologic examination confirmed the similarity between PDX tumor samples and their original patient tissue samples. Interestingly, we also optimized a protocol to generate tumoroids from PDAC PDXs. Leveraging the broad spectrum of disease represented in our collection will facilitate addressing critical research questions, identifying novel therapeutic targets, and ultimately improving patient outcomes of PDAC.

Citation Format: Mariana Yáñez, Enrique Javier Arenas, Teresa Macarulla, Tian Tian, Joaquín Arribas, Sofía Llorente, Carles Fabregat, Marta Escorihuela, Florian Castet, Jessica Querol, Maria Teresa Salcedo. Characterization of a collection of patient-derived xenograft models for pancreatic ductal adenocarcinoma translational research [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C060.
Abstract C065: Base excision repair pathway regulates transcription-replication conflicts in pancreatic ductal adenocarcinoma
Authors: Meng Fan , Singh Anup K. , Li Tiane , Attiyeh Marc , Kohram Fatemeh , Williams Terence , Liu Yilun , Raoof Mustafa
Published: January 2024

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication leading to transcription conflicts (TRCs). Unresolved TRCs can cause lethal DNA damage. Here, we sought to investigate the causal role of oncogenic mutations in regulating TRCs in pancreatic ductal adenocarcinoma (PDAC). Further, we characterize the adaptive pathways that mitigate TRCs for PDAC survival. Human PDAC demonstrated 30-120-fold higher levels of TRC genomic signature compared to breast, colon and lung cancer (p<0.001). Gene expression analysis demonstrated high levels of known TRC resolution factors in human tumors compared to normal tissues. TRCs as measured by RNAPII-PCNA proximity ligation assay were significantly enriched in human PDAC cells (Panc-1, BxPC3, MiaPaca2) compared to immortalized normal HPNE cells (p<0.001). Similarly transcriptomic complexes were enriched in nascent DNA immunoprecipitates from Panc1 cells but not HPNE cells. Ectopic expression of oncogenic KRAS(G12D) in human pancreatic ductal epithelial (HPNE) cells enhanced TRCs, and TRC-related DNA:RNA hybrids (R-loops). Inhibition of KRAS or downstream effectors abrogated TRCs in Panc1 and MiaPaca2 cells. An siRNA screen identified several factors in the base-excision repair (BER) pathway as regulators of TRCs. Sub-lethal exposure to hydrogen peroxide enhanced TRCs, whereas N-acetyl cysteine abrogated TRCs. These findings were validated by a pharmacologic approach using inhibitors of APE1 endonuclease in BER pathway (Methoxyamine and CRT). Mechanistic studies revealed that BER pathway inhibition severely altered RNA polymerase II dynamics at nascent DNA; causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated Chk2-ATR pathway but not Chk1-ATM pathway. Co-treatment with ATR inhibitor (VX970, 10-80nM) and BER inhibitor (methoxyamine, 6-12mM) at clinically relevant doses, synergistically enhanced DNA damage and reduced clonogenic survival in PDAC cells. The study uncovers a novel role of BER pathway defects and oxidative DNA damage in promoting TRCs. Our studies provide mechanistic insights into the regulation of TRCs in PDAC which has implications for genome instability and therapy in PDAC.

Citation Format: Fan Meng, Anup K. Singh, Tiane Li, Marc Attiyeh, Fatemeh Kohram, Terence Williams, Yilun Liu, Mustafa Raoof. Base excision repair pathway regulates transcription-replication conflicts in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C065.
Abstract C086: Investigating resistance to RAS therapies in PDAC models
Authors: Ting Hsiu-Chi , Kim Sun , Park Youngkyu , Deschnes Astrid , Kastan Jonathan , Nigri Jeremy , Tuveson David
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) carries a significantly unfavorable prognosis due to delayed detection and limited therapeutic options, resulting in high mortality rates. The majority of PDAC tumors (>90%) harbor activating mutations in the KRAS oncogene, making KRAS an attractive target for investigating the complex biology of PDAC and identifying potential genetic vulnerabilities that can be exploited for patient treatment. Although small molecules targeting Kras have shown promising results in preclinical and clinical studies of PDAC, the responses have not been durable, and understanding the mechanisms of resistance is a current challenge for the field. To overcome these challenges, we employed two genetic models to mimic Kras inhibition by small molecules. Firstly, using the FPC mouse model, we deleted an endogenous oncogenic KrasG12V allele in mice with measurable PDAC. Secondly, we utilized Auxin-inducible degron 2 (mAID-Auxin) technology to induce acute degradation of Kras proteins, enabling us to evaluate the efficacy of Kras degradation both in vitro and in vivo. Both models led to acute tumor regressions followed by eventual relapse, providing another approach for modeling response and resistance. Acute Kras degradation resulted in a rapid decrease in p-ERK signaling and tumor cell proliferation and alterations in multiple signaling pathways. Sustained degradation of KrasG12D resulted in tumor relapse that predominantly exhibited a mesenchymal phenotype. Intriguingly, we observed several epithelial foci within the relapsed tumors, which displayed reactivated p-ERK signaling. In summary, our study presents an acute ablation model of oncogenic Kras in PDAC, effectively recapitulating the response observed in Kras inhibition both in vitro and in vivo. Furthermore, our model provides insights into the survival mechanism following Kras loss and the mechanisms underlying tumor relapse upon long-term Kras inhibition in PDAC. These findings contribute to our understanding of PDAC biology and offer potential avenues for alternative therapeutic interventions.

Citation Format: Hsiu-Chi Ting, Sun Kim, Youngkyu Park, Astrid Deschnes, Jonathan Kastan, Jeremy Nigri, David Tuveson. Investigating resistance to RAS therapies in PDAC models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C086.
Abstract C093: Dysregulated spliceosomal components promote pancreatic cancer progression
Authors: Wan Ledong , Lin Kuan-Ting , Rahman Mohammad A. , Ishigami Yuma , Kral Alexander J. , Voss Dillon , Wang Zhikai , Jensen Mads A. , Wilkinson John E. , Park Youngkyu , Tuveson David A. , Krainer Adrian R.
Published: January 2024

Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatic ductal adenocarcinoma (PDAC) is not well understood. We found that two proteins involved in different stages of spliceosome assembly contribute to PDAC tumorigenesis by regulating alternative splicing, either through direct or indirect interaction with RNA. First, we showed that the splicing factor SRSF1—an RNA-binding protein involved in early spliceosome assembly—can induce pancreatitis and accelerate KRASG12D-mediated PDAC by activating the MAPK pathway. Moreover, the expression of SRSF1 decreased in morphologically normal pancreatic cells expressing KRASG12D to maintain cellular homeostasis. Second, we found that breast cancer amplified sequence 2 (BCAS2, also known as SPF27)—a spliceosome scaffold protein associated with conformational changes—also contributes to PDAC progression. Although BCAS2 does not bind RNA directly, it can regulate alternative splicing events in a sequence-specific manner by promoting the usage of specific 5’ splice sites. BCAS2 promotes the inclusion of exon 21, which has a weak 5' splice site, in the SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 (SOS1) pre-mRNA, resulting in a more oncogenic isoform. These studies not only improve our understanding of the oncogenic role of aberrant alternative splicing, but also provide insights into the mechanisms of alternative-splicing regulation at different stages of spliceosome assembly.

Citation Format: Ledong Wan, Kuan-Ting Lin, Mohammad A. Rahman, Yuma Ishigami, Alexander J. Kral, Dillon Voss, Zhikai Wang, Mads A. Jensen, John E. Wilkinson, Youngkyu Park, David A. Tuveson, Adrian R. Krainer. Dysregulated spliceosomal components promote pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C093.
Abstract C105: Functional dissection of the basal cell state in pancreatic cancer
Authors: Singhal Anupriya , Styers Hannah , Yan Yan , Joost Simon , Pitter Kenneth , Grbovic-Huezo Olivera , Sahin Hulya , Basturk Olca , Tammela Tuomas
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy with a dismal prognosis. Cancer cell plasticity – the capacity to differentiate and adapt to cell-extrinsic pressure via non-genetic mechanisms – promotes PDAC progression and drives resistance to treatment. Thus, targeting plasticity is a promising therapeutic strategy yet plasticity drivers in PDAC remain poorly understood. Using genetically engineered mouse models driven by oncogenic KrasG12D and loss of p53 (“KPC” model), we profiled primary PDAC tumors using single-cell RNA sequencing and single cell ATAC sequencing. We identified a cancer cell differentiation state that co-expresses both epithelial and mesenchymal programs and has a distinct epigenetic landscape with accessible chromatin across gene sets that mark cancer cell states with divergent phenotypes, suggesting that this cell state is primed for cell state switching. Notably, this high-plasticity cell state (HPCS) signature aligns with a "basal" signature in human PDAC, which associates with poor prognosis and resistance to chemotherapy. To functionally interrogate the HPCS in PDAC progression, we developed a novel lineage-tracing and ablation system allowing (1) visualization of cells in a specific state; (2) timed introduction of a heritable mark allowing us to track cell state progeny; and (3) timed cell state killing via a suicide gene. Lineage-tracing experiments revealed that the HPCS has a robust capacity for differentiation into epithelial/”classical” and mesenchymal states, indicating that the HPCS is functionally plastic and acts as a source of fixed malignant states. Strikingly, targeted elimination of the HPCS over short time periods resulted in tumor collapse, underscoring a critical role in tumor maintenance. Taken together, our data indicates that PDAC harbors a striking dependency on the HPCS, which drives malignant cell state transitions, promotes intra-tumoral diversity, and is critical for tumor maintenance. Our results strongly encourage therapeutic approaches aimed at eradicating this critical subset of cancer cells to improve outcomes in PDAC.

Citation Format: Anupriya Singhal, Hannah Styers, Yan Yan, Simon Joost, Kenneth Pitter, Olivera Grbovic-Huezo, Hulya Sahin, Olca Basturk, Tuomas Tammela. Functional dissection of the basal cell state in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C105.
Abstract C114: Engrailed-1 promotes pancreatic cancer metastasis
Authors: Xu Jihao , Roe Jae-Seok , Lee EunJung , Tonelli Claudia , Somervile Tim , Yao Melissa , Milazzo Joseph , Tiriac Herve , Kolarzyk Anna , Lee Esak , Grem Jeam , Lazenby Audrey , Grunkemeyer James , Hollingsworth Michael , Grandgenett Paul , Borowsky Alexander , Park Youngkyu , Vakoc Christopher , Tuveson David , Hwang Chang-il
Published: January 2024

Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.

Citation Format: Jihao Xu, Jae-Seok Roe, EunJung Lee, Claudia Tonelli, Tim Somervile, Melissa Yao, Joseph Milazzo, Herve Tiriac, Anna Kolarzyk, Esak Lee, Jeam Grem, Audrey Lazenby, James Grunkemeyer, Michael Hollingsworth, Paul Grandgenett, Alexander Borowsky, Youngkyu Park, Christopher Vakoc, David Tuveson, Chang-il Hwang. Engrailed-1 promotes pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C114.
Abstract PR12: Targeting CDK7/9 in basal pancreatic cancer
Authors: Kugel Sita , Kartha Nithya , Gianopulos Jessica E. , Schrank Zach , Cavender Sarah M. , Dobersch Stephanie , Faiyaz Notta , Price David H. , Hsieh Andrew C. , Hingorani Sunil R.
Published: January 2024

Pancreatic ductal adenocarcinoma (PDA) is classified into two distinct subtypes, classical and basal, with the basal subtype predicting worse survival in patients. We hope that with a deeper understanding of the biology that drives these subtypes, we can identify novel subtype-specific therapies. We recently described a novel finding that basal PDAs are uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9. Additionally, we identified that Sirtuin 6 histone deacetylase (SIRT6) expression levels correlate with PDA subtype, showing that basal PDA is low in SIRT6 expression and classical PDA is high through analysis of hundreds of human PDA tumors. Furthermore, we uncovered an important mechanism by which SIRT6 regulation of the integrated stress response (ISR) can control sensitivity of PDA to CDK7/9 inhibitors. By using a variety of in vitro drug assays, genetic manipulation experiments, immunofluorescence, cycloheximide chase experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDA, we were able to show that SIRT6 regulates activating transcription factor 4 (ATF4) protein stability. Therefore, SIRT6 high/classical PDA has a constitutively active ISR, enabling it to recover and survive the stress of CDK7/9 transcriptional inhibition. On the other hand, basal PDA has low SIRT6 which promotes ATF4 protein instability and a nonfunctional ISR, therefore CDK7/9 transcription inhibition leads to apoptosis. Furthermore, we found that similar to intrinsic resistance, acquired resistance to CDK7/9 inhibitors occurs through the loss of basal state drivers and that restoration of these genes re-sensitizes cells to CDK7/9 inhibition. Importantly, this work highlights the role of chromatin modifiers in regulating PDA subtypes and sensitivity to CDK7/9 inhibitors. PDA subtypes have very distinct chromatin landscapes. We have found that classical PDA maintains its epithelial cell state through chromatin regulators like the SETDB1 heterochromatin complex and more specifically the KRAB-Zinc Finger protein ZNF274. Loss or gain of ZNF274 can induce a cell state change in which classical PDA loses its epithelial characteristics and becomes more mesenchymal in nature. Excitingly, this sensitizes cells to CDK7/9 inhibition. Thus, our work demonstrates the importance of cell state and subtype in therapeutic response to CDK7/9 inhibitors in pancreatic cancer.

Citation Format: Sita Kugel, Nithya Kartha, Jessica E. Gianopulos, Zach Schrank, Sarah M. Cavender, Stephanie Dobersch, Notta Faiyaz, David H. Price, Andrew C. Hsieh, Sunil R. Hingorani. Targeting CDK7/9 in basal pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR12.
Safety and Efficacy of Asciminib in Chronic Myeloid Leukemia Patient with Chronic Kidney Diseases: A Case Report
Authors: Alshurafa Awni , Adil Afshan , Yassin Mohamed A.
Published: January 2024

Introduction: Chronic myeloid leukemia (CML) is characterized by the presence of the BCR::ABL1 fusion gene, and the advent of tyrosine kinase inhibitors (TKIs) has revolutionized its therapeutic landscape. Asciminib, a STAMP inhibitor, emerges as a promising option for patients unresponsive or intolerant to multiple conventional TKIs. However, the safety and efficacy of asciminib in individuals with chronic kidney disease remain understudied. Case Presentation: In this report, we detail the case of a 62-year-old patient with CML and stage 3 chronic kidney disease, who faced intolerance to traditional TKIs primarily due to fluid retention. The transition to asciminib therapy resulted in a profound molecular response and did not exacerbate renal function, effectively addressing the fluid retention issue. Conclusion: This case highlights the potential of asciminib as a viable therapeutic alternative for CML patients with chronic kidney disease, particularly those intolerant to standard TKIs. Further research is warranted to establish the broader safety and efficacy profile of asciminib in this patient population.
III Congresso Pan-americano de 1906: Juan Ramón Molina, Ruben Darío e o Brasil – uma perspectiva política
Authors: Elias Neto Jorge , Zerlin Solveig Josefina Villegas , Oliveira Ester Abreu Vieira de
Published: January 2024

A ideia de uma união entre os povos das Américas é de importância histórica. Uma das estratégias voltadas para o ideal pan-americanista foi a criação do Congresso Pan-americano, cuja terceira edição ocorreu no ano de 1906 no Rio de Janeiro. Dois poetas hispano-americanos, o nicaraguense Rubén Darío e o hondurenho Juan Ramon Molina são o nosso fio condutor para discutir as circunstâncias e as posições defendidas pelas nações de língua hispânica, em contraposição aos objetivos dos EUA, esses, em boa medida, apoiados pelos diplomatas brasileiros. Destacamos o protagonismo de Joaquim Nabuco e traçamos uma linha de análise que nos conduz até os nossos dias, levando em conta as perspectivas de autores como Bueno (2012) e Henrich (2017) para nossa abordagem. Salientamos a trajetória de Juan Ramón Molina, poeta pouco discutido em língua portuguesa, bem como suas intervenções relacionadas ao pan-americanismo. Nosso artigo ressalta o conflito de visão do pan-americanismo entre os participantes do Congresso e, principalmente, sua configuração final, dialogando com a análise proposta para a situação atual da América Latina.
El Caribe en la asociación estratégica UE - CELAC: ¿qué esperar tras la III cumbre?
Authors: Laguardia Martínez Jacqueline
Published: January 2024

Este artículo tiene como objetivo el análisis del rol del Caribe en la relación birregional entre Europa y la región de América Latina y el Caribe a través del examen de los mecanismos formales, que articulan las relaciones entre el Caribe y Europa, y de los resultados de la III Cumbre UE-CELAC. Para la investigación se asume una perspectiva caribeña que reconoce los desafíos al desarrollo que distinguen al Caribe en su condición de pequeños Estados insulares. La investigación es de carácter cualitativo y se clasifica como descriptiva-explicativa. Se utilizó una amplia revisión documental que abarcó comunicaciones, declaraciones oficiales, artículos académicos y de opinión publicados en medios reconocidos. En las conclusiones, además de valorarse la contribución real y potencial del Caribe a la Asociación Estratégica UE-CELAC, se incluyen sugerencias para la acción que permita al Caribe elevarse en un papel más protagónico en el marco de la relación birregional, teniendo en cuenta la condición de identidades múltiples de varios territorios caribeños, su inclusión en foros multilaterales con presencia europea y escasa participación latinoamericana, y su liderazgo moral en temas de interés como el cambio climático en un contexto global donde las dinámicas geopolíticas y económicas se han movido desde el Atlántico hacia el Pacífico en perjuicio de Europa, América Latina y el Caribe.
Sesgo de género en las elites políticas de América Latina: claves interpretativas desde una encuesta comparada a académicos
Authors: Serna Miguel
Published: January 2024

El objeto del  artículo es presentar un análisis desde el mundo académico de la percepción de “techos de cristal” y obstáculos de las mujeres para el acceso a puestos jerárquicos e integración a las elites políticas de América Latina. El estudio tuvo como universo de investigación 2.877 académicos de las principales universidades de Argentina, Chile, Brasil, México y Uruguay. Se aplicó una encuesta de género on line conformada por una muestra de 313 expertos en la temática (economistas, contadores, sociólogos, politólogos y CCSS) entre 2019 y 2021. Los resultados aportan desde una mirada de género y comparada de países de académicos sobre la situación de las inequidades de género en la cúspide del poder político, los factores que inciden y el papel de las políticas públicas e instituciones en el reclutamiento discriminado de las elites.
L’épreuve du réel, un moment d’orientation de l’avenir
Authors: Méloni Dominique
Published: January 2024

Choisir une orientation professionnelle à l’adolescence constitue une étape décisive souvent oppressante pour les élèves. Généralement appréhendée comme la nécessité d’un compromis entre les exigences de la réalité et les désirs individuels, la notion de réel fournit d’autres pistes d’analyse qui permettent de mieux saisir l’angoisse suscitée. En engageant la question de la jouissance et du désir, la soumission à un choix d’orientation peut en effet induire une effraction psychique. La reprise de certains moments essentiels de la jeunesse de l’écrivain français André Gide repérés par Lacan permettra de préciser ses implications et fournira des pistes de réflexion pour envisager les modalités d’une issue de l’adolescence à l’occasion du choix d’orientation. Nous verrons alors l’importance que revêt l’énonciation d’une parole autorisatrice pour que le sujet puisse être auteur de sa vie.
Left Atrial Strain to Predict Postoperative Atrial Fibrillation in Patients Undergoing Coronary Artery Bypass Grafting
Authors: Pastore Maria Concetta , Degiovanni Anna , Grisafi Leonardo , Renda Giulia , Sozzani Martina , Giordano Andrea , Salvatici Cosimo , Lorenz Veronica , Pierfelice Francesca , Cappelli Clelia , De Donno Federica , Focardi Marta , Ricci Fabrizio , Benedetto Umberto , Gallina Sabina , Cameli Matteo , Patti Giuseppe
Published: January 2024

BACKGROUND:

Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery being associated with poorer outcomes. Revealing before the operation of left atrial subtle structural/functional abnormalities may help to identify patients at increased risk of POAF. We investigated the role of left atrial strain parameters by preoperative speckle tracking echocardiography as independent predictors of POAF in patients undergoing coronary artery bypass graft.

METHODS:

Consecutive patients undergoing isolated coronary artery bypass graft were prospectively enrolled at three Italian centers. All patients underwent transthoracic echocardiography before the operation. The occurrence of POAF up to discharge was monitored.

RESULTS:

Overall, a total of 310 patients were included. POAF was demonstrated in 103 patients (33%). At receiver operating characteristic curve analysis, lower global peak atrial longitudinal strain (PALS) values significantly predicted the risk of POAF (area under the curve, 0.74;
P
<0.001). The optimal cutoff value for the arrhythmia prediction was a global PALS value <28%, with a specificity of 86% and a sensitivity of 36%. The incidence of POAF was 51% in patients with global PALS <28% versus 14% in those with PALS ≥28% (
P
<0.001), with a POAF-free survival at Kaplan-Meier analysis of 45.4% and 85.7%, respectively (
P
<0.001). At multivariate analysis, a global PALS <28% carried a 3.6-fold higher risk of POAF (hazard ratio, 3.6 [95% CI, 2.2–5.9];
P
<0.001). The risk increase was even higher when PALS <28% was associated with age ≥70 years (adjusted hazard ratio, 11.2 [4.7–26.6],
P
<0.001).

CONCLUSIONS:

A presurgery global PALS <28% is a specific parameter to stratify patients at increased risk of POAF after coronary artery bypass graft. This assessment can be useful to identify patients at higher arrhythmic risk in whom perioperative preventive strategies and stricter monitoring aimed at early diagnosing and treating POAF may be applied.