bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative and Morphology-Based Deep Convolutional Neural Network Approaches for Osteosarcoma Survival Prediction in the Neoadjuvant and Metastatic Settings
Authors: Coudray Nicolas , Occidental Michael A. , Mantilla Jose G. , Claudio Quiros Adalberto , Yuan Ke , Balko Jan , Tsirigos Aristotelis , Jour George 
Published: November 2024

Abstract

Purpose:
Necrosis quantification in the neoadjuvant setting using pathology slide review is the most important validated prognostic marker in conventional osteosarcoma. Herein, we explored three deep-learning strategies on histology samples to predict outcome for osteosarcoma in the neoadjuvant setting.

Experimental Design:
Our study relies on a training cohort from New York University (NYU; New York, NY) and an external cohort from Charles University (Prague, Czechia). We trained and validated the performance of a supervised approach that integrates neural network predictions of necrosis/tumor content and compared predicted overall survival (OS) using Kaplan–Meier curves. Furthermore, we explored morphology-based supervised and self-supervised approaches to determine whether intrinsic histomorphologic features could serve as a potential marker for OS in the neoadjuvant setting.

Results:
Excellent correlation between the trained network and pathologists was obtained for the quantification of necrosis content (R2 = 0.899; r = 0.949; P &lt; 0.0001). OS prediction cutoffs were consistent between pathologists and the neural network (22% and 30% of necrosis, respectively). The morphology-based supervised approach predicted OS; P = 0.0028, HR = 2.43 (1.10–5.38). The self-supervised approach corroborated the findings with clusters enriched in necrosis, fibroblastic stroma, and osteoblastic morphology associating with better OS [log-2 hazard ratio (lg2 HR); −2.366; −1.164; −1.175; 95% confidence interval, (−2.996 to −0.514)]. Viable/partially viable tumor and fat necrosis were associated with worse OS [lg2 HR; 1.287; 0.822; 0.828; 95% confidence interval, (0.38–1.974)].

Conclusions:
Neural networks can be used to automatically estimate the necrosis to tumor ratio, a quantitative metric predictive of survival. Furthermore, we identified alternate histomorphologic biomarkers specific to the necrotic and tumor regions, which could serve as predictors.
Abstract A023: Arachidonic acid metabolism promoting cross resistance in melanoma cells
Authors: Stefanski Casey D. , Erkes Daniel A. , Purwin Timothy J. , Mersky Glenn L. , Kitterman Erica L. , Mustafa Manal , Haj Jelan , Melissaratos Diana , Aplin Andrew E. 
Published: November 2024

Abstract
Melanoma patients initially respond well to first line immunotherapy. However, cross resistance to immunotherapy and BRAF/MEK inhibitor is a clinical challenge for melanoma care. To investigate drug tolerant and resistant mechanisms promoting cross resistance, we analyzed RNA-sequencing and gene set enrichment targeted therapy resistant melanoma cells revealing an enriched arachidonic acid gene signature. Intracellular arachidonic acid levels were increased in drug resistant and drug tolerant melanoma models. Arachidonic acid is enzymatically converted by COX1 and COX2 to prostaglandins, which is subsequently secreted into the microenvironment. Drug tolerant and resistant cells had increased protein expression of COX1 and COX2 concurrently with increased secretion of prostaglandin E2. COX1/2 inhibition and COX2 knockdown in vitro had no effect on cell growth in drug tolerant or resistant cells compared to parental cells. However, secreted prostaglandins are known immunomodulators, thus we explored how COX1/2 inhibition in combination with BRAF inhibitor plus MEK inhibitor affected immune cell infiltration. COX1/2 inhibition increased CD4+ and CD8+ T cell infiltration as compared to BRAF inhibitor plus MEK inhibitor alone. Under constant BRAF inhibitor plus MEK inhibitor treatment, we found that COX1/2 inhibition upon reaching MRD status prevented tumor relapse in vivo and increased survival dependent on an immune system. Future studies will evaluate the importance of arachidonic acid metabolism in promoting cross resistance to immune checkpoint blockade and whether T cell depletion prevents the delayed tumor relapse. Overall, COX1/2 inhibition delayed tumor relapse and survival in an immune-dependent manner and demonstrated a potential cross resistant mechanism.
Citation Format: Casey D. Stefanski, Daniel A. Erkes, Timothy J. Purwin, Glenn L. Mersky, Erica L. Kitterman, Manal Mustafa, Jelan Haj, Diana Melissaratos, Andrew E. Aplin. Arachidonic acid metabolism promoting cross resistance in melanoma cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A023.
Abstract B002: Dynamic response and evolving adaptation of pancreatic cancer cells to the prolonged acidic pH microenvironment
Authors: Wayne Chang Wun-Shaing 
Published: November 2024

Abstract
Solid tumor cells are often immersed in an acidic microenvironment. While many previous studies have investigated the short-term effects of extracellular acidity on tumor cells, little is known about how they adapt to the prolonged acidic microenvironmental stress and then advance to more aggressive stages. By challenging pancreatic tumor cells as an example with continuously and gradually acidified extracellular pH, a variety of cellular characteristics including phenotypic regulation, proliferation rates, autophagic control, metabolic plasticity and metastatic potentials were identified. More detailed evidence regarding the mitochondrial network dynamics and mechanistic control of pancreatic tumor cells in response to the extracellular acidosis will be presented at this conference to emphasize the critical effects of this stress factor as a selection force for tumor adaptation and progression. These findings not only highlight the importance of dynamic response and evolving adaptation of solid tumor cells to the chronic microenvironmental acidity, but also the potential of targeting the 'acid-mediated tumor malignancy' for anticancer therapy.
Citation Format: Wun-Shaing Wayne Chang. Dynamic response and evolving adaptation of pancreatic cancer cells to the prolonged acidic pH microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B002.
Abstract B010: Improving pancreatic cancer image classification with transfer learning: CD45 vs. PANCK
Authors: Thomas Miracle 
Published: November 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is known for its high aggressiveness and is the fourth most common cause of death of cancer-related death in the United States. It is highly malignant and often goes undiagnosed until advanced stages due to its late-onset symptoms, resulting in poor prognosis. Using quantitative analyses of histological features, such as the expression of prognostic biomarker, can provide valuable insight to guide treatment decisions, monitor disease progression and predict outcomes. Previous researchers have found that CD45 and PANCK play a huge role in characterizing the tumor microenvironment of PDAC. One study using single-cell RNA sequencing compared the microenvironments of healthy pancreata and pancreatic tumors, revealing differences in cellular composition. Tumor samples showed a higher proportion of immune cells, including CD45+ cells, compared to heathy samples and utilized PANCK to differentiate between epithelial and non-epithelial cells. This study aims to enhance the accuracy of classifying pancreatic cancer pathological images based on prognostic markers using transfer learning techniques. We curated and pre-processed a dataset of pancreatic cancer pathological images with different prognostic markers. Using the pre-trained convolutional neural network (CNN) model VGG16, we fine-tuned it with our dataset to better differentiate between two prognostic markers, CD45 and PANCK. The model's performance was evaluated using a similarity matrix to illustrate distinctions among the two prognostic markers. Our results demonstrate that the transfer learning approach significantly improves classification accuracy, achieving confusion matrix validation results of 90% between CD45 and PANCK prognostic markers. SSIM values were relatively low, highlighting the ability of our model to differentiate between the two prognostic markers. The low SSIM value also shows variability within the two prognostic markers, indicating heterogeneity in structural changes due to pancreatic cancer. These findings indicate that transfer learning can be a powerful tool for improving the classification of pathological images and that there is notable variability in the structural features associated with different prognostic markers in pancreatic cancer.
Citation Format: Miracle Thomas. Improving pancreatic cancer image classification with transfer learning: CD45 vs. PANCK [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B010.
Abstract B019: Regulatory macrophages contribute to tumor cell plasticity in colorectal cancer metastases
Authors: Cottam Matthew A. , Mirza Muhammad B. , Arner Emily N. , Siddiqui Marium , Lipscombe Clare , Hatem Zaid , Beckermann Katy E. , Idrees Kamran 
Published: November 2024

Abstract
Metastatic disease is the common cause of death in colorectal cancer. To better understand the cellular landscape of colorectal metastasis, we profiled primary tumors and liver, lung, and peritoneal metastases using single-cell RNA sequencing. Our analysis revealed a subset of tumor epithelial cells with a highly plastic transcription profile and, inversely, low expression of stemness markers. Tumor cells with plasticity markers were spatially enriched at the tumor- stroma interface with exposure to tissue microenvironmental factors. Cell-free malignant ascites, which recapitulates the tumor microenvironment, impaired expression of proliferation and stem- like markers in favor of plasticity markers and enhanced migration of tumor cells. Furthermore, Co-culture of colorectal tumor cells with CD11b+ macrophages isolated from malignant ascites from patients was sufficient to recapitulate tumor cell plasticity. Profiling of tumor-associated macrophages identified enrichment for a lipid-handling features and high spatial correlation with plastic tumor cells. Taken together, we demonstrate that tumor-associated macrophages contribute to disease progression through development of pro-malignant features.
Citation Format: Matthew A. Cottam, Muhammad B. Mirza, Emily N. Arner, Marium Siddiqui, Clare Lipscombe, Zaid Hatem, Katy E. Beckermann, Kamran Idrees. Regulatory macrophages contribute to tumor cell plasticity in colorectal cancer metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B019.
Abstract B020: Lean adipocyte-secreted oxylipin, 9S-HODE, triggers ferroptosis and protects against obesity-accelerated breast cancer
Authors: Curtin Meghan , Maschek J. Alan , Wang Guoying , Lum David , Cox James E. , Hilgendorf Keren I 
Published: November 2024

Abstract
Approximately 1 in 8 women will develop breast cancer in their lifetime, and over 40,000 women in the United States die from breast cancer every year. Post-menopausal breast cancer risk and mortality rates are exacerbated by those who are classified as obese, such that a 5-unit increase in body mass index is linked to a 12% increase in risk. The rising rates of obesity make understanding the link between obesity and the incidence, progression, and mortality of breast cancer of high priority. Obesity is marked by an expansion of white adipose tissue, which accounts for 90% of the breast cancer microenvironment. While several studies have identified paracrine factors secreted by obese adipose tissue that promote tumorigenesis, the role that lean adipose tissue plays in breast cancer progression remains underexplored. In this study, I screened the secretome of primary adipocytes isolated from multiple fat pads from both lean and obese mice for the ability to modulate the growth of breast cancer cell lines across multiple different subtypes. I discovered a potent role of lean mammary adipocytes in selectively inhibiting breast cancer cells in vivo and in vitro. This inhibitory function is specific to lean, mammary adipocytes, as the secretomes of obese mammary adipocytes or adipocytes isolated from visceral fat depots do not inhibit breast cancer cell growth. Further, I discovered that the lean mammary adipocytes, but not obese adipocytes, secrete an oxylipin called 9S-HODE, an oxidized metabolite derived from the essential fatty acid linoleic acid. I show that lean adipocytes and 9S- HODE inhibit breast cancer cell growth by triggering ferroptosis. However, normal breast epithelial cells are protected from 9(S)-HODE-induced ferroptosis by transiently growth- arresting and rapidly forming lipid droplets. We propose that lean adipocytes actively inhibit the growth of breast cancer cells by secreting the ferroptosis inducer 9(S)-HODE, and that in patients with obesity, breast cancer is accelerated, at least in part, due to the loss of 9(S)-HODE- mediated tumor suppression.
Citation Format: Meghan Curtin, J. Alan Maschek, Guoying Wang, David Lum, James E. Cox, Keren I Hilgendorf. Lean adipocyte-secreted oxylipin, 9S-HODE, triggers ferroptosis and protects against obesity-accelerated breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B020.
Abstract B026: Pancreatic tumor extracellular vesicles induce perineural invasion in vitro via IL- 8/CCL2
Authors: Gregory Emory A , Powers Isabel , Baek Inha , Dugan Reagan , Jamshidi-Parsian Azemat , Griffin Robert J. , Song Younghye 
Published: November 2024

Abstract
Pancreatic cancer (PDAC) remains a pre-eminent cause of cancer-related death with perineural invasion (PNI), i.e., cancer cell infiltration of nerves, contributing to high morbidity rates. Glial Schwann cells (SC) are activated by tumor signaling to produce chemical gradients, re-direct cancer cells, and accelerate PNI. Tumor extracellular vesicles (EV) have been implicated in cancer-nerve crosstalk; however, their role in activating SCs during PDAC PNI is unclear. In this study, we explored tumor EVs as initiators of SC-dependent PDAC PNI using tissue engineered modeling platforms. NanoSight Nanoparticle Tracking Analysis and Western blot confirmed the presence of non-contaminated EVs. Liquid chromatography-mass spectrometry characterized healthy (HPNE) and cancer cell (PANC-1) EV cargoes, and QIAGEN Ingenuity Pathway Analysis also exposed potential EV targets. SCs (sNF96.2) were embedded in an optimized decellularized nerve hydrogel and cultured with EVs ± cargo-function-blocking monoclonal antibody. SC phenotype was assessed using Luminex® multiplex assays and immunofluorescence. Subsequently, EV-treated SCs were co-cultured with healthy or cancer cells, and invasion was further probed using Transwell® assays. Proteins associated with IL-8 signaling were upregulated in tumor EVs versus healthy EVs. Tumor EVs significantly activated SCs to produce cytokines related to PNI, namely CCL2, in an IL-8-dependent manner. Tumor EV/IL-8-activated SCs facilitated significantly greater invasion in cancer cells compared to healthy cells, which was reduced by neutralizing IL-8 from tumor EVs or CCL2 in SC- conditioned media. These findings provide evidence of a potential mechanism in which PDAC EVs reprogram SCs to amplify PNI and necessitate further pre-clinical investigations with increased biodiversity targeting EVs for PDAC therapeutics.
Citation Format: Emory A Gregory, Isabel Powers, Inha Baek, Reagan Dugan, Azemat Jamshidi-Parsian, Robert J. Griffin, Younghye Song. Pancreatic tumor extracellular vesicles induce perineural invasion in vitro via IL- 8/CCL2 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B026.
Abstract B028: The Role of cDC1 Gene Signatures in gastric cancer prognosis and immune microenvironment modulation
Authors: han Song-hee 
Published: November 2024

Abstract
Background and Aim: Gastric cancer (GC) continues to be a major global health burden, with a growing body of evidence highlighting the critical role of conventional type 1 dendritic cells (cDC1s) within the tumor microenvironment. This study aims to elucidate the prognostic significance of cDC1-associated genes—CD141, XCR1, CLEC9A, CADM1, and BTLA—in gastric cancer, as well as to explore the biological mechanisms that underpin their effects on patient outcomes. Materials and Methods: We conducted a comprehensive analysis of RNA- seq data from The Cancer Genome Atlas (TCGA-STAD) and Gene Expression Omnibus (GEO) datasets, focusing on the expression profiles of five cDC1-related genes. Patients were stratified into high and low expression groups based on a defined cDC1 gene signature. To assess the impact of these signatures, we utilized gene set variation analysis (GSVA) to examine relevant oncogenic pathways and performed Kaplan-Meier survival analysis along with Cox proportional hazards modeling to evaluate their prognostic value. Results: Our findings demonstrate that patients exhibiting a high cDC1-related gene signature had significantly worse overall and disease-free survival within the TCGA-STAD cohort. Further analysis revealed marked differences in CD8+ T cell infiltration and cytotoxic activity between the high and low cDC1 signature groups. Additionally, the high cDC1 signature group was strongly associated with upregulated expression of immune checkpoint proteins and the activation of oncogenic pathways, indicating a highly immunosuppressive tumor microenvironment. Conclusions: This study suggests that the cDC1-related gene signature may serve as a potent prognostic biomarker in gastric cancer, offering new insights into the complex interactions between the tumor and immune microenvironment. These results could pave the way for innovative therapeutic strategies that target the immune landscape in gastric cancer, potentially improving patient outcomes.
Citation Format: Song-hee han. The Role of cDC1 Gene Signatures in gastric cancer prognosis and immune microenvironment modulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B028.
Abstract C024: MPLA+IFNg-activated tumor-associated macrophages alter fibroblast composition
Authors: Sun Lijuan , Liu Bodu , Zhao Yixin , Egeblad Mikala 
Published: November 2024

Abstract
In a previous study, we developed a strategy to reprogram tumor-associated macrophages (TAMs) and induce a collaborative innate-adaptive immune response by combining monophosphoryl lipid A (MPLA) with IFNγ. However, we also observed downregulation of extracellular matrix (ECM)-associated genes in MPLA+IFNγ-treated mammary tumors, indicating that the combination treatment impacts the tumor microenvironment beyond just the immune cells. In this study, we investigated how MPLA+IFNg treatment modulates the tumor ECM, with a particular focus on fibroblasts-the major ECM-producing cells. Using scRNA-seq to profile mammary carcinomas, we identified six macrophage populations (C1q+, Ccr2+, Spp1+, Lyz+, mt+ and ki67+ TAMs) and two fibroblast populations (Cd34+ and a-SMA+ fibroblasts) in MMTV-PyMT tumor. MPLA+IFNγ treatment increased the numbers and percentages of Lyz+ TAMs and Cd34+ fibroblasts, while the numbers and percentages of Spp1+ TAMs and α-SMA+ fibroblasts were decreased by the treatment. Thus, MPLA+IFNγ treatment induced significant changes in both macrophage and fibroblast populations. Further analysis revealed an unusual gene expression pattern in Lyz+ TAMs. Mgst1 and Gng12 expression was detected in Lyz+ TAMs at levels comparable to those in fibroblasts, despite these genes typically being expressed in fibroblasts but not in macrophages of normal human tissues. However, to our surprise, MPLA+IFNγ treatment did not significantly increase Mgst1 and Gng12 expression of mono-cultured TAMs or bone marrow-derived macrophages, suggesting that these genes were not directly upregulated by MPLA+IFNγ treatment. Instead, the Mgst1 and Gng12 transcripts may have originated from engulfed fibroblasts. In addition, following MPLA+IFNγ treatment, more iNOS+ macrophages (which we previously identified as tumoricidal macrophages) were found in very close proximity to α-SMA+ fibroblasts. To directly test whether MPLA+IFNg-treated TAMs kill and engulf fibroblasts, we performed ex vivo co-cultures of TAMs and fibroblasts. Following MPLA+IFNγ treatment, TAMs effectively killed and engulfed the fibroblasts, whereas minimal fibroblast engulfment was observed in the control co-cultures. Our data suggest that tumoricidal MPLA+IFNγ-treated TAMs can regulate the ECM of tumors by targeting and eliminating the major ECM-producing cells, the fibroblasts. Ongoing studies are determining the functional consequences of the TAM-mediated regulation of fibroblasts and ECM composition.
Citation Format: Lijuan Sun, Bodu Liu, Yixin Zhao, Mikala Egeblad. MPLA+IFNg-activated tumor-associated macrophages alter fibroblast composition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C024.