tbuckley/cabot-search huggingface dataset:
Abstract B094: The role of paraspeckles and splicing regulation in driving basal-like pancreatic cancer
Authors: Zamira G. Soares, Emily Berry, Dakarai Esgdaille, Jennifer Twardowski, Stephano S. Mello
Journal: Cancer Research (2024)

Abstract The basal-like pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of mesenchymal PDAC that resists treatment and has a poor prognosis. Understanding the mechanisms driving basal-like PDAC biology will be essential for development of treatment strategies for this aggressive tumor. We have previously shown that loss of the tumor-suppressive non-coding RNA Neat1 recapitulate the phenotype of Arid1a-deficient mice (a component of the SWI/SNF chromatin remodeling complex) in a mouse model for PDAC, with loss of exocrine pancreatic identity and development of acinar- and ductal-derived lesions (Mello et al., 2017), suggesting that Neat1 and Arid1a may share a common molecular mechanism. We now demonstrate that the loss of these two divergent genes induce the emergence of basal-like PDAC. This provides an opportunity to probe for shared features specific to Neat1- and Arid1a-deficient PDAC, as compared to PDAC in which both genes are functional. Notably, our data indicate that both Neat1- and Arid1a-deficient pancreatic cells fail to form nuclear paraspeckles, i.e. structures implicated in the retention of RNA splicing factors. Consistent with this idea, we also find significantly increased exon-skipping, including a sub-set of such events shared between Neat1- and Arid1a-deficient PDAC. In addition, nucleotide sequence motifs associated with exon-skipping locations suggest involvement of RNA splicing factors known to accumulate in paraspeckles, such as Srsf1, Srsf2, Srsf10, Rbm38, Dazap1 and others. We also show that, upon genetic or pharmacological attenuation of splicing regulator function, basal-like PDAC develop epithelial features, reminiscent of mesenchymal-epithelial transition, reduce both their proliferation and migration potential and undergo cell death. Our findings provide an important opportunity to elucidate the molecular pathways that link aberrant RNA splicing and paraspeckle deficiency to basal-like PDAC, providing new insight for the development of mechanism-based novel PDAC treatment strategies to improve patient outcome. Citation Format: Zamira G. Soares, Emily Berry, Dakarai Esgdaille, Jennifer Twardowski, Stephano S. Mello. The role of paraspeckles and splicing regulation in driving basal-like 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 B094.
Abstract C086: Investigating resistance to RAS therapies in PDAC models
Authors: Hsiu-Chi Ting, Sun Kim, Youngkyu Park, Astrid Deschnes, Jonathan Kastan, Jeremy Nigri, David Tuveson
Journal: Cancer Research (2024)

Abstract 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 (&amp;gt;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 B112: Single-cell profiling of neoplastic cell populations in a KRAS-initiated zebrafish pancreatic cancer model
Authors: Somer M. Matar, Britton C. Goodale, Xiaoying Liu, Annie Katanga, Nicole F. Gallien, Sandra Blazquez, Direna Alonso-Curbelo, Steven D. Leach
Journal: Cancer Research (2024)

Abstract While the majority of human pancreatic cancers are classified as ductal adenocarcinomas, the cell of origin of these tumors remains uncertain and many tumors are comprised of dedifferentiated cell types, making it imperative to understand the full spectrum of neoplastic differentiation and how it is regulated. We have developed a new zebrafish model of pancreatic cancer driven by tissue-specific expression of UAS:mK02-KRASG12D under the regulation of a Ptf1a:Gal4/VP16 transcriptional driver. Transgenic zebrafish generate mixed tumors comprised histologically of mixed acinar and ductal elements, providing the opportunity to interrogate specific transcriptional and epigenetic modifiers responsible for regulating neoplastic pancreatic cellular differentiation. Single-cell RNA sequencing of these tumors has confirmed neoplastic cell populations expressing exclusively acinar and ductal markers, as well as distinct clusters expressing markers of both cell lineages. Screening a panel of 21 unique chromatin modifiers and chromatin readers for differential expression in these distinct cell clusters reveals hdac9b to be upregulated in the progenitor-like ductal population. Gain- and loss-of-function genetic studies will be used to determine the functional role of hdac9b in generating distinct neoplastic cell differentiation states. We are also generating pseudo-time trajectory inferences to further determine the directionality of differentiation states in these cells. By generating new insights into regulation of distinct differentiation states in pancreatic cancer, we hope that new strategies for therapeutic manipulation of neoplastic cell differentiation will emerge. Citation Format: Somer M. Matar, Britton C. Goodale, Xiaoying Liu, Annie Katanga, Nicole F. Gallien, Sandra Blazquez, Direna Alonso-Curbelo, Steven D. Leach. Single-cell profiling of neoplastic cell populations in a KRAS-initiated zebrafish pancreatic cancer model [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 B112.
Abstract B013: Effect of aging on pancreatic cancer progression
Authors: Deepika Bhullar, Swetha Maganti, Yijuan Zhang, Cheska Marie Galapate, Rabi Murad, Peter D. Adams, Cosimo Commisso
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive disease mainly seen in older adults. Most pancreatic cancer cases occur in individuals who are over the age of 60, and the risk continues to increase with each decade of life, with the median age at diagnosis for PDAC being around 70 years old. Why age is a significant risk factor in PDAC remains unanswered question. To examine the impact of organismal age on PDAC progression, we used a syngeneic orthotopic mouse model of PDAC in young and old animals. We found that the growth of primary tumors was significantly enhanced in the older mice indicating that organismal age can influence tumor progression. We also found that older mice had increased metastatic tumor burden in the liver, intestines and diaphragm. To gain a comprehensive view of how age might be affecting PDAC progression, we performed transcriptomics on the tumors derived from young or old animals. Strikingly, using gene set enrichment analysis (GSEA), we found that epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) molecule deposition-related signatures were enriched in the old mice, suggesting that the enhanced metastasis that we observed in old animals could be related to changes in the ECM. Moreover, we also identified various immune cell signatures that were enriched in the old or young mice, suggesting that the immune contexture dramatically changes depending on the age of the organism. These ECM and immune cell signatures were validated histologically. Based on these preliminary data, our working hypothesis is that the tumor stroma in old versus young organisms plays a critical role in PDAC progression, and we are employing various in vitro and in vivo techniques to test this idea. Citation Format: Deepika Bhullar, Swetha Maganti, Yijuan Zhang, Cheska Marie Galapate, Rabi Murad, Peter D. Adams, Cosimo Commisso. Effect of aging on 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 B013.
Abstract IA16: Feeding the flames of pancreatic cancer
Authors: Mandar D. Muzumdar
Journal: Cancer Research (2024)

Abstract Obesity is a metabolic state of energy excess and a risk factor for over a dozen cancer types, including pancreatic adenocarcinoma, the third leading cause of cancer-related death in the United States. Due to the rising worldwide prevalence of obesity, decoding the mechanisms by which obesity promotes tumor initiation and early progression is a societal imperative and could broadly impact human health. The pancreas plays a central role in response to feeding, secreting digestive enzymes (from exocrine cells) and hormones (from endocrine cells) to aid in the absorption and cellular uptake of essential nutrients and to regulate glucose homeostasis. Therefore, the pancreas is uniquely positioned to be the great integrator of how diet and obesity fuel disease, including cancer. Leveraging a combination of genetic models, diverse high fat diet panels, and timed-feeding paradigms in mice, we have demonstrated that the quantity, quality, and possibly even the kinetics of feeding prime the pancreas for cancer. We have further uncovered mechanisms by which feeding stress reprograms pancreatic endocrine-exocrine signaling and lipid metabolism to drive tumorigenesis. Targeting obesity-driven hormone dysregulation and altered cellular metabolism through precision pharmacologic or nutritional interventions may aid in extinguishing the development of pancreatic cancer and potentially other obesity-associated cancers. Citation Format: Mandar D. Muzumdar. Feeding the flames of 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 IA16.
Abstract B040: Neural control of cancer-associated fibroblasts in PDAC
Authors: Jeremy Nigri, Wenjun Lan, Sangeeta S Chavan, Youngkyu Park, Jeremy Borniger, Kevin J Tracey, David A Tuveson
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) poses a formidable challenge to public health, with a dismal 5-year survival rate and a projected rise as the second leading cause of cancer-related deaths by 2030. The pathogenesis of PDAC involves a robust desmoplastic reaction and a complex tumor microenvironment (TME), constituting up to 80% of the tumor volume. The TME is a heterogeneous mixture of cells, including cancer-associated fibroblasts (CAFs), immune cells, endothelial cells, and neurons, which all interact and contribute to disease progression. However, the precise interplay between the tumor-associated nerves and PDAC development remains unclear. It is known that neural remodeling within the tumor microenvironment are closely associated with intense neuropathic pain, metastasis, and shortened patient survival. The prevalence of nerve fibers present in the dense desmoplastic stroma of PDAC tumors suggest a potential interaction between neurons and stromal cells, particularly CAFs, through various paracrine signaling mechanisms, influencing CAF behavior and facilitating neural remodeling, ultimately driving PDAC progression. Our investigation revealed that the neurotransmitter noradrenaline, induces calcium signaling and prompt contraction in pancreatic stellate cells (PSCs). Preliminary in vitro findings indicate that this calcium signaling is mediated by alpha 1 adrenergic receptors. Whole-mount 3D imaging mouse PDAC tissues, indicates a spatial organization of adrenergic neurons in immediate proximity to neoplastic cells and cancer-associated fibroblasts. Moreover, our study demonstrated that noradrenaline and alpha 1 agonists modulate extracellular matrix (ECM) production and cytokine secretion in PSCs and CAFs. Finally, we discovered that chemical ablation of the sympathetic nervous system significantly suppresses tumor growth while promoting metastasis, underscoring the critical role of the noradrenergic system in tumor development. Collectively, our findings propose that noradrenergic neurons possess the capacity to influence CAF behavior, opening new avenues of investigation to unravel the intricate crosstalk between neural regulation and tumor progression in PDAC. Citation Format: Jeremy Nigri, Wenjun Lan, Sangeeta S Chavan, Youngkyu Park, Jeremy Borniger, Kevin J Tracey, David A Tuveson. Neural control of cancer-associated fibroblasts in PDAC [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 B040.
Abstract A115: Collective invasion facilitates liver metastasis in pancreatic ductal adenocarcinoma
Authors: Jennifer R. Eng, Carl Pelz, Koei Chin, Sam Sivagnanam, Link M. Jason, Dove Keith, Lisa Coussens, Rosalie C. Sears
Journal: Cancer Research (2024)

Abstract Fifty percent of PDAC patients present with distant metastasis and face a dismal prognosis of 8 to 11 months. However, patients with lung metastases have better prognosis than patients with metastatic spread to other sites. In our PDAC metastasis cohort, patients with lung-only metastasis survived longer than patients with liver metastasis, despite sharing the same tumor subtype. To understand features of the primary tumor linked to metastatic site, we generated a novel gene signature for primary organotropism (pORG) that distinguishes primary tumors that developed liver metastasis from those that developed lung metastasis, independent of known tumor subtypes. Our pORG signature predicts survival independently of transcriptional subtype, genetic alterations and clinicopathological variables and in a validation cohort consisting of TCGA pancreatic cancer. Primary tumors with high pORG scores, i.e., liver-tropic primaries, have increased transcriptomic signatures of proliferation and replication stress whereas low pORG tumors have increased lymphocyte gene expression. To validate our findings, we generated cyclic immunofluorescence multiplex imaging data from 34 primary tumors. As anticipated, single cell image analysis revealed high B and T cell infiltration in low-pORG tumors, and increased proliferation and replication stress foci in high-pORG tumors. Intriguingly, malignant cells from high pORG tumors had an increased fraction KRT19-high tumor cells relative to low pORG tumors and were distinctly epithelial in appearance. To reconcile the metastatic behavior of high pORG tumors with their apparent enrichment for epithelial-state cells, we hypothesized that liver-tropism was associated with a partial epithelial-to-mesenchymal transition (EMT) state and metastasis via collective invasion. Bulk transcriptional analysis of 200 PDAC primary tumors revealed a distinct subset of high pORG tumors have increased expression of markers linked to partial EMT and collective invasion, including RAB11a, Rho-like GTPases, and proteases MMP7 and KLK7. Our results support a model of E-cadherin internalization facilitating partial EMT and collective invasion. Current efforts include in-vitro characterization of migration modes in patient-derived cell lines and organoids. Our work suggests unique and targetable tumor intrinsic features linked to organotropism in PDAC. Citation Format: Jennifer R. Eng, Carl Pelz, Koei Chin, Sam Sivagnanam, Link M. Jason, Dove Keith, Lisa Coussens, Rosalie C. Sears. Collective invasion facilitates liver metastasis 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 A115.
Abstract C113: The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma
Authors: Jillian S. Weissenrieder, Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, J. Kevin Foskett
Journal: Cancer Research (2024)

Abstract In spite of many new developments in cancer treatments and targeted therapies over the past few decades, outcomes for pancreatic ductal adenocarcinoma (PDAC) patients continue to be poor. Calcium signaling and mitochondrial function are known to contribute to cancer outcomes in many paradigms, yet much remains unknown in the context of PDAC. The mitochondrial Ca2+ uniporter, MCU, is the main route by which mitochondria can take up Ca2+ into the mitochondrial matrix, where it drives metabolic activity in the tricarboxylic acid cycle and promotes ATP synthesis by the electron transport chain. Our previous work suggests that Ca2+ flux from the endoplasmic reticulum (ER) into the mitochondria at mitochondria-associated membranes (MAMs) may be important to drive malignancy. Here, we show that MCU expression is associated with poor outcomes in PDAC patients and disease progression in murine organoid models of cancer development. Further, deletion of Mcu in murine KPC cells results in ablation of mitochondrial Ca2+ uptake, which reduces growth, proliferation, and clonogenicity. Tumor growth and metastatic colonization are also reduced in orthotopic implantation models, with some KPCY-McucKO models failing to develop primary lesions. This suggests that MCU, and thus mitochondrial Ca2+, play an important role in tumor growth. Critically, we here elucidate a heretofore unknown relationship between ER-to-mitochondrial Ca2+ flux through Mcu and epithelial to mesenchymal transition (EMT), an important process that contributes to poor outcomes in PDAC. To this end, McucKO associates with reduced basal Snail expression and reduced TGFβ secretion, and McucKO clones have a more epithelial morphology than their isogenic, Mcu-expressing counterparts. Both stable expression of Snail and treatment with TGFβ are able to rescue growth, mobility, and clonogenic deficits in McucKO cell lines to levels comparable to isogenic, Mcu-expressing cell lines. Uptake assays, metabolomics, isotope tracing, and mRNA-Seq have enabled us to elucidate metabolic and transcriptional rewiring induced by Snail and TGFβ treatment which may promote cell survival and proliferation despite the lack of Mcu. This work has important implications for potential targeting of Ca2+ signaling in the context of PDAC. Citation Format: Jillian S. Weissenrieder, Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, J. Kevin Foskett. The mitochondrial calcium uniporter supports epithelial to mesenchymal transition 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 C113.
Abstract B026: αvβ5 Integrin serves as a tumor-specific marker for immunosuppressive regulatory T cells in pancreatic cancer
Authors: Yuki Kunisada, Kodai Suzuki, Norio Miyamura, Shingo Eikawa, Tatiana Hurtado de Mendoza, Evangeline S. Mose, Caisheng Lu, Yukihito Kuroda, Erkki Ruoslahti, Andrew M. Lowy, Kazuki N. Sugahara
Journal: Cancer Research (2024)

Abstract Regulatory T cells (Tregs) contribute to the immunosuppressive nature of pancreatic ductal adenocarcinoma (PDAC). Systemic depletion of Tregs can enhance anti-tumor T cell immunity, but can also cause unwanted autoimmune complications. A tumor-specific Treg-targeted therapy that effectively and safely enhances anti-tumor immunity for PDAC treatment remains an unmet need. We have recently found that αvβ5 integrin is expressed on Tregs that reside in the PDAC, but not those in the spleen, suggesting that the integrin can serve as a targetable marker for tumor-resident Tregs. Indeed, long-term treatment with the iRGD tumor-penetrating peptide, which effectively targets αvβ5+ cells in PDAC tissue, depleted Tregs in a tumor-specific manner leading to a significant expansion of CD8+ T cells in transgenic and syngeneic PDAC mouse models. αvβ5+ Tregs were induced from both naïve CD4+ T cells and naturally occurring Tregs. T cell receptor stimulation was found to be the common inducer of αvβ5+ Tregs. αvβ5+ Tregs formed a subpopulation of CCR8+ Tregs, which are preferentially found in the tumor tissue of various cancer types. Our most recent data show that the αvβ5 integrin marks a highly immunosuppressive fraction of the CCR8+ Tregs, suggesting that targeting αvβ5+ Tregs can lead to effective depletion of immunosuppressive Tregs in a tumor-specific manner. Citation Format: Yuki Kunisada, Kodai Suzuki, Norio Miyamura, Shingo Eikawa, Tatiana Hurtado de Mendoza, Evangeline S. Mose, Caisheng Lu, Yukihito Kuroda, Erkki Ruoslahti, Andrew M. Lowy, Kazuki N. Sugahara. αvβ5 Integrin serves as a tumor-specific marker for immunosuppressive regulatory T cells 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 B026.