tbuckley/cabot-search huggingface dataset:
Abstract A020: Molecular basis of immune suppressive microenvironment specified by cancer-associated fibroblasts in pancreatic cancer
Authors: Kazunori Aoki, Hironori Fukuda, Eri Hashimoto, Kosuke Arai
Journal: Cancer Research (2024)

Abstract Despite constant efforts to improve treatment, the prognosis remains poor, with an overall survival rate of 6% (ranges from 2% to 9%) due to lack of efficient chemotherapy, radiotherapy, and targeted therapy. Immune checkpoint inhibitors (ICIs) has been reported to be effective in various solid cancers, such as melanoma, lung cancer, and renal cell carcinoma. However, pancreatic ductal adenocarcinoma (PDAC) is resistant against ICIs. The responsiveness of immune therapy is mainly determined by immune tumor microenvironment (TME) composed of tumor-infiltrating lymphocytes (TIL) and stromal cells. PDAC possesses unique TME, which is abundant of fibrosis, termed of desmoplasia, and the role of fibrosis in constructing immune suppressive TME remains unclear. First, in this study, to examine the immunological characteristics of TME, we constructed an integrated data base of TIL profiling, RNA-seq and whole exome seq using 31 fresh resected tissues of PDAC. An unsupervised clustering of based on numbers and percentages of 12 TIL types analyzed by flow cytometry showed that PDAC was divided into 2 types of cluster (myeloid cell-, T cell-dominant type), and the prognosis of myeloid type was significantly poorer than T cell-type. Myeloid type contained the high frequency of myeloid cell lineage including monocytes, macrophages and myeloid-derived suppressor cells (MDSC). Only MDSCs were significantly associated with poor prognosis among various immune cell types. Furthermore, gene enrichment analysis identified activated and suppressed pathways in each immune type, and the immune-related pathways were significantly down-regulated in myeloid cell-dominant type. Then, to understand the characteristics of MDSCs infiltrated into pancreatic cancer tissues, single cell RNA-seq with surgical specimens was performed, and the analysis showed that a specific subtype of MDSCs infiltrated into cancer tissues. In addition, activation status of cancer-associated fibroblasts (CAFs) was related with MDSC recruitment and activation, indicating that the interaction between MDSCs and CAFs is crucial to create MDSC-rich TME. Inhibition of interaction between MDSCs and CAFs is expected to overcome immunosuppressive TME can be a novel immunotherapy in PDAC. Citation Format: Kazunori Aoki, Hironori Fukuda, Eri Hashimoto, Kosuke Arai. Molecular basis of immune suppressive microenvironment specified by 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 A020.
Abstract A031: Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma
Authors: Benjamin N. Christopher, Lety Reyes, Reeder Robinson, Lena Golick, Nathan Dolloff
Journal: Cancer Research (2024)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of only 10%, and limited treatment options exist. Immune checkpoint inhibitors are effective in a variety of cancer types; however, the complex immunosuppressive tumor microenvironment (TME) of PDAC is a significant barrier to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors from humans and mouse models. MDSCs suppress effector T cell function and promote the expansion of other immunosuppressive cell types. This led us to hypothesize that targeting tumor MDSCs would be an effective therapeutic strategy for PDAC and enhance the efficacy of T cell based immunotherapy. Our preliminary data and the work from others shows that CXCR2 ligands such as CXCL8/IL-8, CXCL5/ENA78, and CXCL1/GROα are the most abundant soluble factors secreted by PDAC cells. CXCR2 ligands are critical for the homing of myeloid cells to sites of injury in cutaneous wound healing, suggesting that dysregulated secretion of CXCR2 chemokines in PDAC may mimic a wound healing response that attracts myeloid cells and promotes the expansion of MDSCs and an immunosuppressive TME. To test this hypothesis, we have designed and produced multiple drug-conjugated CXCR2 ligand-based engineered proteins to target and eliminate MDSCs from PDAC tumors. We are referring to these novel biotherapeutic molecules as Ligand Drug Conjugates (LDCs). We have demonstrated binding, internalization, induction of signaling, and cytotoxicity of these LDCs to CXCR2 expressing myeloid cells. Our data suggests that our engineered proteins are superior binders and activators of CXCR2 axis signaling compared to WT CXCR2 ligands. Utilizing CXCR2 knockin models we demonstrated that the cytotoxicity of our LDCs is CXCR2 dependent. In vivo, we are utilizing the KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse model of PDAC, which we've shown in preliminary studies to, like human PDAC, support an abundance of MDSCs in tumors as well as secondary lymphoid organs such as the spleen. We anticipate that this study will demonstrate the therapeutic potential and actionability of targeting MDSCs and will provide novel biotherapeutic drug candidates that will ultimately improve immunotherapy outcomes in patients with PDAC. Citation Format: Benjamin N. Christopher, Lety Reyes, Reeder Robinson, Lena Golick, Nathan Dolloff. Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells 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 A031.
Abstract A114: Low-dose carbon monoxide halts pancreatic cancer metastasis
Authors: Tiantian Zhang, George Zhang, Xiang Chen, Zhengming Chen, Adrian Y. Tan, Anthony Lin, Cheryl Zhang, Guoan Zhang, Jenny Xiang, Erika Hissong, Yao-Tseng Chen, Nancy Du
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90% of pancreatic cancer cases. Over the last 30 years, standard care of chemotherapy only extends the survival of metastatic pancreatic cancer patients for a few months. Despite years of remarkable innovations in cancer treatment, the 5-year survival rate of PDAC has remained dismal. The recalcitrant nature of PDAC to available treatments highlights an urgent need for novel therapeutics in order to substantially increase survival. Carbon monoxide (CO) is produced endogenously in humans and has been established as an important, biologically active signaling molecule. Accumulating evidence suggests the therapeutic applications of safe, low-dose CO for various diseases. We evaluate the therapeutic effect of CO on pancreatic cancer progression. We show that 250 ppm CO inhibits migration of pancreatic cancer. We demonstrate that low-dose CO suppresses metastasis of PDAC in an orthotopic mouse model of liver metastasis and a spontaneous PDAC metastasis mouse model after the removal of primary tumor xenograft tumors. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Altogether, low-dose CO therapy inhibits pancreatic cancer cell migration, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis. Citation Format: Tiantian Zhang, George Zhang, Xiang Chen, Zhengming Chen, Adrian Y. Tan, Anthony Lin, Cheryl Zhang, Guoan Zhang, Jenny Xiang, Erika Hissong, Yao-Tseng Chen, Nancy Du. Low-dose carbon monoxide halts 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 A114.
Abstract IA20: Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer
Authors: Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A. LaBella, Deepavali Chakravarti, Denise J. Spring, Yan Xia, Ronald A. DePinho
Journal: Cancer Research (2024)

Abstract Oncogenic KRAS (KRAS*) is a signature mutation in pancreatic ductal adenocarcinoma (PDAC). While genetic extinction or pharmacological inhibition of KRAS* elicits anti-tumor responses in preclinical models and patients, we and others have identified cancer cell intrinsic (YAP, RTKs) and paracrine immune-mediated (TGFb) mechanisms enabling KRAS* bypass and tumor recurrence. Here, we explored the potential role of cancer associated fibroblasts (CAFs) as contributors to mechanisms driving KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS* independent tumor regrowth is supported. We showed that genetic extinction or pharmacological inhibition of KRAS* results in upregulation of ERBB2 and ERBB3 expression in human and murine cancer cell models. We demonstrated that CAF-derived NRG1 supports KRAS*-dependent tumor growth. These insights prompted genetic depletion or pharmacological inhibitions studies targeting ERBB2/3 or NRG1, which showed abolition of KRAS* bypass and synergy with KRASG12D inhibitor in mouse and human PDAC models. Thus, CAFs via the NRG-ERBB2/3 paracrine axis provide yet another mechanism enabling KRAS* inhibitor therapy resistance, providing a highly actionable combination therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients. Citation Format: Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A. LaBella, Deepavali Chakravarti, Denise J. Spring, Yan Xia, Ronald A. DePinho. Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas 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 IA20.
Abstract B071: Tumor Treating Fields (TTFields) together with PARP inhibitors for treatment of pancreatic cancer cells
Authors: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Eyal Dor-On, Puru Lamichhane, Adi Haber, Moshe Giladi, Yoram Palti
Journal: Cancer Research (2024)

Abstract Purpose/Objectives: Pancreatic cancer remains a leading cause of cancer-related death, with limited treatment options available for the advanced stage. PARP inhibitors (PARPi) are effective treatment options in patients with germline BRCA mutations. Recently, TTFields – electric fields that disrupt cellular processes critical for cancer cell viability – have been shown to induce a state of BRCAness in various cancer types. The objective of this study was to examine possible sensitization of BRCA wild type pancreatic cancer cell lines to PARP inhibition by the application of TTFields. Materials/Methods: BxPC3 and AsPC1 BRCA wild type, human pancreatic cancer cells were treated for 48 and 72 h, respectively, with TTFields (intensity of 1 and 0.7 V/cm RMS, respectively) at a frequency of 150 kHz using the inovitro device. TTFields were applied to the cells alone or together with various concentrations of the PARP inhibitors niraparib or olaparib. Cell count, colony formation, and apoptosis were measured at treatment end. Results: Applying TTFields to pancreatic cell lines resulted in cytotoxicity, anti-clonogenic effect, and induction of apoptosis. PARP inhibitors also demonstrated such effects, in a dose-dependent fashion. Co-application of TTFields enhanced the effects of PARP inhibitors. Conclusions: The results show a benefit for concomitant application of TTFields and PARPi in pancreatic cancer, potentially due to the BRCAness state induced by TTFields. The data suggest TTFields may enhance PARP inhibition efficacy in the absence of background BRCA mutations. Citation Format: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Eyal Dor-On, Puru Lamichhane, Adi Haber, Moshe Giladi, Yoram Palti. Tumor Treating Fields (TTFields) together with PARP inhibitors for treatment of pancreatic cancer cells [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 B071.
Abstract B076: Development of novel gemcitabine-modified miRNA mimics for pancreatic ductal adenocarcinoma
Authors: Jingfang Ju
Journal: Cancer Research (2024)

Abstract Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with PDAC in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a new treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a). In a panel of PDAC cell lines, we found that Gem-miR-15a induces cell cycle arrest and apoptosis, and these mimics are potent inhibitors with single digit nM IC50 up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a. Compared to Gem, we also found that our Gem-modified miRNA mimics exhibit enhanced efficacy by over several hundred fold less than Gem in patient-derived PDAC organoids. Gem-miR-15a was able to eliminate Gem resistant PDAC cells and organoids. In addition, Gem-miR-15a was able to be delivered to PDAC cells without the aid of delivery vehicle, a major advancement in nucleic acid based medicine. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of muti-targeted Gem-modified miRNAs as a novel treatment strategy for PDAC. Citation Format: Jingfang Ju. Development of novel gemcitabine-modified miRNA mimics for 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 B076.
Abstract C053: Autophagy regulates MAT2A in response to hypoxia in pancreatic cancer cells
Authors: Yang Yang, Wenping Wang, Gilles Rademaker, Mirunalini Ravichandran, Jingjie Hu, Alexander Li, Joseph D. Mancias, Jessie Yanxiang Guo, Rushika M. Perera
Journal: Cancer Research (2024)

Abstract Methionine adenosyltransferase 2A (MAT2A) is an essential enzyme responsible for biosynthesis of S-adenosylmethionine, a methyl-group donor of various methyltransferases. Pancreatic ductal adenocarcinoma PDAC is characterized by severe hypoxia and upregulates autophagy and lysosomal biogenesis to enhance nutrient recycling and stress resistance. Here we show that a subset of MAT2A is targeted via the autophagy pathway for degradation by the lysosome under normoxia in PDAC cells, but is subsequently protected against degradation under hypoxia. Mechanistically, we show that the autophagy cargo receptor SQSTM1 (p62) binds to MAT2A in a ubiquitin-dependent manner under normoxia to regulate its autophagic capture. Under hypoxic conditions, stabilized MAT2A potentially facilities increased flux of methionine towards increased SAM, suggesting that protection of MAT2A against lysosomal degradation might enable alterations in methionine metabolism that drive epigenetic and metabolic adaptation to stress. Citation Format: Yang Yang, Wenping Wang, Gilles Rademaker, Mirunalini Ravichandran, Jingjie Hu, Alexander Li, Joseph D. Mancias, Jessie Yanxiang Guo, Rushika M. Perera. Autophagy regulates MAT2A in response to hypoxia in pancreatic cancer cells [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 C053.
Abstract C020: Unconvering the hidden immunosuppressive landscape in pancreatic ductal adenocarcinoma
Authors: Guhan Qian, Hongrong Zhang, Aine Knott, Jon Zettervall, Ingunn Stromnes, Paolo Provenzano
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDA) is one of the deadliest forms of cancer with an extremely low survival rate. Despite the success of therapeutic T cells in hematologic cancers, many solid tumors, including PDA, remain unresponsive with such therapies, partly due to its mechanically complex, dense, and immunosuppressive stroma. Therefore, understanding the dynamic interplay between therapeutic T cells and the tumor microenvironment (TME) is crucial for revealing engineering targets for next-generation immunotherapies. We approach this problem with genetically engineered KPC (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-1-Cre) mouse models that recapitulates PDA disease progression and stromal dynamics. Within live tumor slices from primary tumors, we are defining how stromal components such as dense collagen fiber networks and tumor-associated macrophages (TAMs) orchestrate an immunosuppressive landscape. We employ multiphoton laser scanning microscopy (MPLSM) to generate multiphoton excitation of fluorescence (cell dyes and immunofluorescence) and second harmonic generation (SHG) for collagen fibers to acquire multidimensional data (x, y, z, c, t) of T cell migration and interaction within the TME. We subsequently reveal T cell migration and interaction as a function of its physical and biological ECM components using advanced computer vision and machine learning algorithms based on the Clustered Random Convolutional Kernel Transform (cROCKET), revealing a hidden landscape in the feature space. Perturbations to the TME in KPC mice with CCR2 inhibitor CCX598 (in vivo) and clodronate liposomes (ex vivo) deplete CD11b+ myeloid cells, resulting in altered behaviors of the infiltrating T cells. Anti-PD-1 monoclonal antibody neutralizes the PD-1/PD-L1 axis in T cells, resulting in enhanced migration and infiltration in tumor slices. Citation Format: Guhan Qian, Hongrong Zhang, Aine Knott, Jon Zettervall, Ingunn Stromnes, Paolo Provenzano. Unconvering the hidden immunosuppressive landscape 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 C020.
Abstract B023: Hypoxia supports CAF-mediated epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma
Authors: Karl Kowalewski, Matthew Lazzara
Journal: Cancer Research (2024)

Abstract The pancreatic ductal adenocarcinoma (PDAC) microenvironment is populated by distinct subtypes of cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) that synthesize and remodel the stromal matrix and inflammatory CAFs (iCAFs) that secrete cytokines and growth factors. Subpopulations of CAFs reside in regions of tumor hypoxia, which may play a role in determining CAF behaviors. We tested the hypothesis that iCAFs preferentially drive ductal cell epithelial-mesenchymal transition (EMT), which promotes PDAC chemoresistance, and that hypoxia promotes the iCAF phenotype. Cell-cell communication analysis using publicly available single-cell RNA sequencing (scRNA-seq) data of human tumors indicated that iCAFs secrete growth factors predicted to promote ductal cell EMT. This inference was confirmed in experiments showing that PDAC cells exhibit stronger EMT in response to conditioned medium from iCAFs than from myCAFs. Publicly available scRNA-seq data further indicated a correlation between hypoxia and the iCAF phenotype. qRT-PCR and immunofluorescence microscopy confirmed that hypoxia promotes the iCAF phenotype, and conditioned medium experiments demonstrated the preferential ability of hypoxic CAFs to utilize an NFκB-dependent pathway to secrete cytokines that promote EMT. A screen of 430 kinase inhibitors nominated specific growth factors that we validated to be EMT-inducing and generated by hypoxic CAFs. Finally, iterative indirect immunofluorescence imaging (4i) of tumor sections from KrasLSL-G12D/+; Trp53LSL-R172H/+, Pdx1-Cre; Rosa26YFP/YFP (KPCY) mice and quantitative image analysis demonstrated a spatial correlation in PDAC tumors between mesenchymal neoplastic cells and hypoxic CAFs. Our results raise the intriguing possibility that hypoxia cooperates with CAFs to promote EMT in PDAC and identify drug targets whose antagonism may interfere with a PDAC-stromal signaling process that promotes chemoresistance. Citation Format: Karl Kowalewski, Matthew Lazzara. Hypoxia supports CAF-mediated epithelial-mesenchymal transition 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 B023.