Cause Of Cancer Death Research Articles

Overexpression of PDSS2-Del2 in HCC promotes tumor metastasis by interacting with macrophages

Hepatocellular carcinoma (HCC) is one of the most frequent solid tumors worldwide. According to the Global Cancer Statistics 2020, liver cancer remains the third cause of cancer death globally. Despite significant advances in systemic therapy, HCC still has one of the worst prognoses due to its frequent recurrence and metastasis. Previously we found that PDSS2-Del2 (prenyl diphosphate synthase subunit 2 with exon 2 deletion), a novel variant of PDSS2, could promote HCC metastasis and angiogenesis via activating NF-κB. In this study, we elucidate a novel mechanism by which PDSS2-Del2 enhances HCC metastasis. The overexpression of PDSS2-Del2 in HCC cells promotes the ubiquitination and degradation of SKOR1, consequently heightening SMAD3 phosphorylation. Subsequently, the expression and secretion of MST1 (macrophage stimulatory protein 1) are upregulated, resulting in enhanced recruitment of macrophages into tumor tissues where they differentiate into M2-type macrophages. Co-culture with PDSS2-Del2 overexpressed HCC cells activated the PI3K/AKT signaling pathway in macrophages, and more MMP2 and MMP9 were secreted, which facilitated HCC cell dissemination. Our study elucidates a novel molecular mechanism by which PDSS2-Del2 promotes HCC metastasis, which may contribute to the development of effective HCC clinical treatment and prevent tumor metastasis. Furthermore, MST1 could be a potential therapeutic target, and MST1 inhibitors might be integrated into clinical practice for HCC patients with high expression of PDSS2-Del2.

Incidence rates of soft tissue sarcoma among U.S. military servicemen: Comparison with the rates in the general U.S. population.

Soft tissue sarcoma (STS) is one of the most frequently diagnosed cancers among men younger than age 30 years and a leading cause of cancer death in men younger than age 40 years. The military may be more exposed to STS risk factors and have generally better health and health care access than the general population, which may relate to lower cancer risk and/or early detection. This study compared STS incidence between servicemen and men in the general U.S. Data were from the Department of Defense's Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program. Subjects were active-duty servicemen in ACTUR and men in SEER aged 18-59 years diagnosed with STS from 1990 to 2013. Age-adjusted rates, incidence rate ratios (IRR), and 95% CIs were calculated. STS incidence rates were lower in ACTUR than SEER overall (IRR=0.86 [0.78-0.93]), for 18- to 39-year-old men (IRR=0.78 [0.70-0.86]), by race (White: IRR=0.85 [0.77-0.95]; Black: IRR=0.77 [0.63-0.94]), for sites other than skin/connective/soft tissue (IRR=0.49 [0.37-0.63]), other specified histologies (IRR=0.84 [0.71-0.98]), and unspecified histology (IRR=0.57 [0.38-0.82]). Rates were lower in ACTUR for regional (IRR=0.37 [0.28-0.47]) and distant metastases (IRR=0.58 [0.43-0.76]), even when race and age stratified. However, rates were higher in ACTUR for 40- to 59-year-old men (IRR=1.25 [1.04-1.48]) and localized tumors (IRR=1.16 [1.04-1.29]). Lower STS rates among servicemen may relate to better health and early detection and treatment of STS-associated conditions within the military health system, which provides universal care. Higher rates among 40- to 59-year-old servicemen may result from greater cumulative military-related exposures.

Monitoring central nervous system tumour metabolism using cerebrospinal fluid

Central nervous system (CNS) tumours are the most common cancer cause of death in under 40s in the UK, largely because they persist and recur and sometimes metastasise during treatment. Therefore, longitudinal monitoring of patients during and following treatment must be undertaken to understand the course of the disease and alter treatment plans reactively. This monitoring must be specific, sensitive, rapid, low cost, simple, and accepted by the patient. Cerebrospinal fluid (CSF) examination obtained following lumbar puncture, already a routine part of treatment in paediatric cases, could be better utilised with improved biomarkers. In this review, we discuss the potential for metabolites in the CSF to be used as biomarkers of CNS tumour remission, progression, response to drugs, recurrence and metastasis. We confer the clinical benefits and risks of this approach and conclude that there are many potential advantages over other tests and the required instrumentation is already present in UK hospitals. On the other hand, the approach needs more research investment to find more metabolite biomarkers, better understand their relation to the tumour, and validate those biomarkers in a standardised assay in order for the assay to become a clinical reality.

"Undruggable KRAS": druggable after all.

The three RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in cancer. KRAS is the predominant isoform mutated in cancer and is most prevalently mutated in major causes of cancer deaths including lung, colorectal, and pancreatic cancers. Despite extensive academic and industry efforts to target KRAS, it would take nearly four decades before approval of the first clinically effective KRAS inhibitors for the treatment of KRAS mutant lung cancer. We revisit past anti-KRAS strategies and painful lessons learned and then focus on the rapidly evolving landscape of direct RAS inhibitors, resistance mechanisms, and potential combination treatments.

Daidzein Inhibits Non-small Cell Lung Cancer Growth by Pyroptosis.

Non-Small-Cell Lung Cancer (NSCLC) represents the leading cause of cancer deaths in the world. We previously found that daidzein, one of the key bioactivators in soy isoflavone, can inhibit NSCLC cell proliferation and migration, while the molecular mechanisms of daidzein in NSCLC remain unclear. We developed an NSCLC nude mouse model using H1299 cells and treated the mice with daidzein (30 mg/kg/day). Mass spectrometry analysis of tumor tissues from daidzein-treated mice identified 601 differentially expressed proteins (DEPs) compared to the vehicle-treated group. Gene enrichment analysis revealed that these DEPs were primarily associated with immune regulatory functions, including B cell receptor and chemokine pathways, as well as natural killer cell-mediated cytotoxicity. Notably, the NOD-like receptor signaling pathway, which is closely linked to pyroptosis, was significantly enriched. Further analysis of key pyroptosis-related molecules, such as ASC, CASP1, GSDMD, and IL-1β, revealed differential expression in NSCLC versus normal tissues. High levels of ASC and CASP1 were associated with a favorable prognosis in NSCLC, suggesting that they may be critical effectors of daidzein's action. In NSCLC-bearing mice treated with daidzein, RT-qPCR and Western blot analyses showed elevated mRNA and protein levels of ASC, CASP1, and IL-1β but not GSDMD, which was consistent with the proteomic data. In summary, this study demonstrated that daidzein inhibits NSCLC growth by inducing pyroptosis. Key pathway modulators ASC, CASP1, and IL-1β were identified as primary targets of daidzein. These findings offer insights into the molecular mechanisms underlying the anti-NSCLC effects of daidzein and could offer dietary recommendations for managing NSCLC.

GI cancer mortality in participants in low dose CT screening for lung cancer with a focus on pancreatic cancer

Lung cancer, the leading cause of cancer deaths globally, has better survival rates with early detection. Annual low-dose CT (LDCT) screenings are recommended for high-risk individuals due to age and smoking. These individuals are also at risk for other cancers. Our study explores gastrointestinal (GI) cancer mortality in lung cancer screening participants and the potential of LDCT screenings to detect pancreatic cancer. We utilized data from a prospective multi-institutional cohort study, the International Early Lung Cancer Action Project (I-ELCAP). We analyzed GI cancer deaths among participants in New York State (1992–2010), exploring demographics and GI cancer distribution. Radiologists retrospectively reviewed pancreatic cancer cases within 24 months post-LDCT, comparing findings with original reports. Among 10,150 participants, 189 died from GI cancers; mean age 75, mostly male smokers. Pancreatic cancer (41.8%) led, followed by esophageal (17.5%) and colon cancer (16.9%). Median time between baseline LDCT and death was 116 months (9.7 years). 82/189 (43.4%) participants died within 5 years of their last LDCT screening, with pancreatic cancer again prominent (45.1%). In 79 pancreatic cancer deaths, 17.7% occurred within 24 months post-LDCT. A re-review identified previously undetected pancreatic findings, with 4 out of 14 participants (28.6%) showing abnormalities. This underscores the potential of lung cancer screening programs to provide insights beyond lung health. This study of over 10,000 participants in a lung cancer screening program reveals that they are at risk for GI cancer deaths, particularly pancreatic cancer. Re-reviews of LDCT scans revealed previously undocumented pancreatic findings in a third of participants who died from pancreatic cancer, underscoring the need to identify, document, and follow up on these findings.

An in-silico approach to target Breast cancer with novel phytochemicals

Aging leads to the manifestation of various diseases. Cancer being one of the major illness that is associated with the age. Breast cancer is still a relatively global health concern as the leading cancer cause of death among women. The current study also utilizes an in-silico approach to discover and characterize new phytochemicals as potential therapeutic agents to breast cancer. Here, we explore the molecular basis driving the makeup of breast cancer, with an emphasis on the PI3K/AKT/mTOR pathway, a well-known signaling cascade implicated in cell growth and therapy response. Two candidates (Thalidasine (-8.80 Kcal/mol) and 7-Epiclusianone (-8.62 Kcal/mol)) were found to be promising leads displaying high binding affinity and therapeutic potential through screening a diverse library of phytochemicals against key breast cancer target proteins. These phytochemicals exhibit diverse antineoplastic effects as cell proliferation, angiogenesis, and metastasis inhibitors, and/or as inducers of apoptosis. Besides, their ability to specifically target breast cancer stem cells and to increase sensitivity to traditional therapies make them an appealing option for breast cancer adjuvant therapy. Taken together our data suggest that these phytochemicals should be further studied alone and in novel nano formulations that enhance bioavailability and reduce toxicity. This study adds to the evidence for the potential role of natural products in breast cancer and the role of lifestyle in cancer prevention.

Characterization of a drug resistant MCF-7 breast cancer cell line developed by repeated cycles of 5-Fluorouracil (5-FU) therapy

Breast cancer accounts for 14% of cancer fatalities and 23% of all cancer diagnoses, making it the most common cause of cancer death among women and one of the most frequently diagnosed cancers. This disease is a life-threatening public health concern because of its significant influence on the general population. Therefore, further molecular research is required to determine its prognosis and create tailored treatments. Since it closely resembles mammary epithelium, the human breast cancer cell line MCF-7, which expresses genes for oestrogen, progesterone, and glucocorticoid receptors, is the most appropriate in vitro model for cancer research. Resistant cell lines were created by repeatedly cultivating MCF-7 wild-type cells in media containing 5-fluorouracil, a first-line treatment for breast cancer. The resistant cell lines were found to be cross-resistance to other anticancer medications in addition to being resistant to 5-fluorouracil, according to the in vitro MTT cytotoxicity assay.

Deep learning-based classifier for carcinoma of unknown primary using methylation quantitative trait loci.

Cancer of unknown primary (CUP) constitutes between 2% and 5% of human malignancies and is among the most common causes of cancer death in the United States. Brain metastases are often the first clinical presentation of CUP; despite extensive pathological and imaging studies, 20%-45% of CUP are never assigned a primary site. DNA methylation array profiling is a reliable method for tumor classification but tumor-type-specific classifier development requires many reference samples. This is difficult to accomplish for CUP as many cases are never assigned a specific diagnosis. Recent studies identified subsets of methylation quantitative trait loci (mQTLs) unique to specific organs, which could help increase classifier accuracy while requiring fewer samples. We performed a retrospective genome-wide methylation analysis of 759 carcinoma samples from formalin-fixed paraffin-embedded tissue samples using Illumina EPIC array. Utilizing mQTL specific for breast, lung, ovarian/gynecologic, colon, kidney, or testis (BLOCKT) (185k total probes), we developed a deep learning-based methylation classifier that achieved 93.12% average accuracy and 93.04% average F1-score across a 10-fold validation for BLOCKT organs. Our findings indicate that our organ-based DNA methylation classifier can assist pathologists in identifying the site of origin, providing oncologists insight on a diagnosis to administer appropriate therapy, improving patient outcomes.

Recent trends and therapeutic potential of phytoceutical-based nanoparticle delivery systems in mitigating non-small cell lung cancer.

Lung cancer is the leading cause of cancer death globally, with non-small cell lung cancer accounting for the majority (85%) of cases. Standard treatments including chemotherapy and radiotherapy present multiple adverse effects. Medicinal plants, used for centuries, are traditionally processed by methods such as boiling and oral ingestion, However, water solubility, absorption, and hepatic metabolism reduce phytoceutical bioavailability. More recently, isolated molecular compounds from these plants can be extracted with these phytoceuticals administered either individually or as an adjunct with standard therapy. Phytoceuticals have been shown to alleviate symptoms, may reduce dosage of chemotherapy and, in some cases, enhance pharmaceutical mechanisms. Research has identified many phytoceuticals' actions on cancer-associated pathways, such as oncogenesis, the tumour microenvironment, tumour cell proliferation, metastasis, and apoptosis. The development of novel nanoparticle delivery systems such as solid lipid nanoparticles, liquid crystalline nanoparticles, and liposomes has enhanced the bioavailability and targeted delivery of pharmaceuticals and phytoceuticals. This review explores the biological pathways associated with non-small cell lung cancer, a diverse range of phytoceuticals, the cancer pathways they act upon, and the pros and cons of several nanoparticle delivery systems.

Evaluation of TP53TG1 and PANDA lncRNAs expression in association with adjuvant chemotherapy response in the peripheral blood of invasive ductal carcinoma patients.

Breast cancer is the most common malignancy in women. Breast cancer, the second leading cause of cancer deaths, affects 2.1 million women each year and is estimated to have killed 627,000 women worldwide in 2018. Unfortunately, the age of onset of this cancer in our country IRAN is about 10 years lower than the global average and is close to 45 years. Chemotherapy is one of the basic treatments for cancer. Predicting the benefits of chemotherapy is challenging. Studies are now underway to use gene expression tests to pinpoint patients who are most likely to benefit from adjuvant chemotherapy. In the present study, the expression of two long non-coding RNAs TP53TG1 and PANDA in the blood of breast cancer patients before and after receiving chemotherapy compared with this amount in the blood of normal people using Real-Time RT PCR technique to find a meaningful relationship ¬ Compared statistically. Compared to normal samples, the expression level of TP53TG1 in the blood of patients was reduced. Although it was not statistically significant. Its expression also increased after receiving chemotherapy. Compared to normal samples, the expression of PANDA in the blood of patients was increased, which was statistically significant. Also, its expression decreased after receiving chemotherapy. These findings suggest that PANDA and TP53TG1 expression levels may be possible markers associated with tumorigenesis and may also be considered as possible indicators of response to chemotherapy.

Systemic treatment of hepatocellular carcinoma secondary to non-alcoholic fatty liver disease.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with 15% of cases arising on a background of non-alcoholic fatty liver disease (NAFLD). NAFLD is a heterogenous condition ranging from fatty liver to cirrhosis and is itself a growing global problem, with estimated worldwide prevalence of 50% in 2040. Pathophysiology of NAFLD-HCC is not well understood, there are no dedicated screening programs, and there have been no clinical studies of anti-cancer treatments in this population specifically. However, the NAFLD-HCC population appears different than other aetiologies - patients tend to be older, diagnosed at more advanced stages, have more comorbidities, and overall worse prognosis. Understanding of best treatment options for this group of patients is an urgent unmet clinical need. This narrative review discusses NAFLD-HCC pathophysiology and systemic treatment, and offers suggestions for future directions in this therapy area.

Experiences of women living with cervical cancer in Ghana: challenges and coping strategies

BackgroundCervical cancer is a leading cause of morbidity and mortality among women globally. The condition is both preventable and treatable yet remains a leading cause of cancer death in Ghana. This study aims to explore the unique experiences of women living with cervical cancer with a focus on the challenges and coping strategies.MethodsThe study employed a qualitative approach with an exploratory, descriptive design. This study was conducted among women with cervical cancer aged 18 years and above who have been diagnosed with the disease for at least 3 months. A total of 16 participants were purposively sampled based on the eligibility criteria and individually interviewed using a semi-structured guide. The six-step technique for qualitative analysis by Braun and Clarke guided data analysis.ResultsMost participants resorted to self-medication, over-the-counter drugs and herbal preparations as a first line of defense against the disease. The presence of cervical cancer affected participants’ physical and mental well-being. Other challenges included financial burden and frequent equipment breakdowns which affected patients’ treatment. Participants adopted different coping strategies such as taking blood tonic, increased rest and sleep, spiritual prayers and recreational activities. Family members, friends, the church and health workers provided support in the area of finance, advice, meal preparation and house chores, prayers and counseling to participants.ConclusionsCervical cancer affects the quality of life of many women and their significant others. The condition puts a lot of financial burden on its victims and there is the need for a system to reduce the burden on patients. It is recommended that the treatment of cervical cancer should be covered by the National Health Insurance Scheme to ease the financial burden on patients. There is a need for expansion of access to cervical cancer treatment across the country to reduce patients’ burden and relieve the pressure on the few pieces of equipment at the current treatment centres.

The role of PM2.5 exposure in lung cancer: mechanisms, genetic factors, and clinical implications.

Lung cancer is one of the most critical global health threats, as the second most common cancer and leading cause of cancer deaths globally. While smoking is the primary risk factor, an increasing number of cases occur in nonsmokers, with lung cancer in nonsmokers (LCNS) now recognized as the fifth leading cause of cancer mortality worldwide. Recent evidence identifies air pollution, particularly fine particulate matter (PM2.5), as a significant risk factor in LCNS. PM2.5 can increase oxidative stress and inflammation, induce genetic alterations and activation of oncogenes (including the epidermal growth factor receptor, EGFR), and contribute to lung cancer progression. This review summarizes the current understanding of how exposure to PM2.5 induces lung carcinogenesis and accelerates lung cancer development. It underscores the importance of prevention and early detection while calling for targeted therapies to combat the detrimental effects of air pollution. An integrated approach that combines research, public health policy, and clinical practice is essential to reduce the lung cancer burden and improve outcomes for those affected by PM2.5 exposurrre.

A Community-Engaged Research Study to Inform Tailored Programming for Smoking Cessation and Lung Cancer Screening Among At-Risk LGBTQ+ Elders.

Purpose. Lung cancer is the leading cause of cancer death, with most cases attributable to cigarette smoking. Many communities within the lesbian, gay, bisexual, transgender and queer/questioning (LGBTQ+) umbrella have high rates of smoking, but focused lung cancer prevention is limited. Our objective was to utilize a community-based participatory research (CBPR) approach to guide the development of a program focused on lung cancer prevention in LGBTQ+ elders. Methods. Through community partnerships, we recruited participants who self-identified as LGBTQ+ and were eligible for lung cancer screening (LCS) to participate in semi-structured qualitative discussions with complementary surveys. Qualitative guides were developed to collect data on determinants of smoking cessation and LCS and to elicit feedback on interventions to support lung cancer prevention through a tailored approach to patient navigation. Qualitative data were analyzed using rapid templated analysis to elucidate themes. Results. The 21 enrolled participants had diverse sexual and gender identities and 57% were of minoritized race/ethnicity. Most (81%) had experience with smoking cessation but few (10%) had undergone LCS. Overall themes suggest interest in personalized (to individuals), tailored (to the LGBTQ+ community) and integrated longitudinal programs to support lung cancer prevention. Themes suggest strong endorsement of focused messaging to LGBTQ+ persons and reducing stigma related to LGBTQ+ identity and smoking. Conclusions. Themes highlight the need for integrated tobacco and LCS programming which can provide longitudinal support, and ideally, center community settings and peer support. This formative work will be utilized to adapt a patient navigation program to assist screen-eligible LGBTQ+ elders.

Identification of the Oncogenic Role of the Circ_0001326/miR-577/VDAC1 Cascade in Prostate Cancer.

Prostate cancer (PCa) is one of the leading causes of cancer death among men worldwide. Circular RNAs (circRNAs) have been implicated in the pathogenesis of PCa. However, the precise action of circ_0001326 in PCa malignant progression is still unknown. The levels of circ_0001326, miR-577 and voltage dependent anion channel 1 (VDAC1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, colony formation, apoptosis, migration and invasion were evaluated by the Cell Counting Kit-8 (CCK-8), EdU staining, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Targeted relationships among circ_0001326, miR-577 and VDAC1 were confirmed by dual-luciferase reporter assays. Xenograft experiments were performed to detect the role of circ_0001326 in tumor growth. Our data revealed that circ_0001326 was overexpressed in PCa tissues and cells. Circ_0001326 depletion repressed PCa cell proliferation, migration, and invasion and enhanced apoptosis in vitro, as well as hampered tumor growth in vivo. Mechanistically, circ_0001326 directly targeted miR-577, and VDAC1 was directly targeted and suppressed by miR-577. Moreover, the effects of circ_0001326 knockdown on PCa cell functional behaviors were mediated by miR-577. VDAC1 silencing phenocopied miR-577 overexpression in regulating PCa cell functional behaviors in vitro. Furthermore, circ_0001326 regulated VDAC1 expression through sponging miR-577. Our findings showed that circ_0001326 regulated PCa cell functional behaviors at least partly through targeting the miR-577/VDAC1 axis.

Quantitative distribution of essential elements and non-essential metals in breast cancer tissues by LA-ICP-TOF-MS.

Breast cancer (BC) is the leading cause of cancer death among women worldwide, making the discovery and quantification of new biomarkers essential for improving diagnostic and preventive strategies to limit dissemination and improve prognosis. Essential trace metals such as Fe, Cu, and Zn may play critical roles in the pathophysiology of both benign and malignant breast tumors. However, due to the high metabolic activity and reduced element selectivity of cancer cells, also non-essential elements may be taken up and may even be implicated with disease progression. This study investigates the spatial distribution and concentrations of both essential and non-essential elements in breast tissues, assessing their potential for diagnostic applications. Laser ablation (LA)-inductively coupled plasma-mass spectrometry (ICP-MS) with a time-of-flight (ToF) mass analyzer (LA-ICP-ToF-MS) was used to inquire the distribution of almost all elements across the periodic table and their abundance in metastatic (n = 11), non-metastatic (n = 7), and healthy (n = 4) breast tissues. Quantification was achieved using gelatine-based standards for external calibration to quantitatively map various elements. Overall, the Fe, Cu, Zn, Sr, and Ba levels were significantly increased in tumor samples with Sr and Ba showing strong correlation, likely due to their similar chemistry. Comparison of calibrated LA-ICP-ToF-MS data with a histologic staining demonstrated the possibility to clearly differentiate between varioustissue types and structures in breast tissues such as tumor niche and stroma. The levels of thestudied elements were significantly higher inthe tumor niche areas compared to the stroma, and for Fe, a significant accumulation was observed in the tumor niche areas from the metastatic patient group relative to the levels found in the same areas of the non-metastatic group.

First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy against Pancreatic Cancer.

Pancreatic cancer, with its increasing incidence and lowest 5-year survival rate, is predicted to become the second leading cause of cancer deaths by 2030. Current clinical trials have shown limited improvement, highlighting the need for new therapies. The sigma-2 receptor (S2R), with roles in tumor progression, is a target for novel thiosemicarbazones (TSCs). FA4 has shown potent activity against pancreatic cancer in vivo. We synthesized complexes of FA4 with Cu(II) and Pt(II), and compared their efficacy with complexes of the non-S2R-targeting TSC 1. TSC-Cu exhibited over 50-fold higher in vitro cytotoxicity than TSCs-Pt, which was less active than TSCs. FA4-Cu induced apoptotic cell death via ER and mitochondrial stress showing more potent activity than FA4. This in vitro effect was replicated in the preclinical PANC-1 model, where FA4-Cu was more potent than FA4, 1, and 1-Cu. These results support further exploration of FA4-Cu as a potential therapy for pancreatic cancer.

Abstract A006: Investigating the effects of fibroblasts derived from the primary versus the metastatic organ on 3D biomimetic models of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the United States with a 5-year survival rate of only 13%. Early diagnosis is very difficult and thus 53% of patients are diagnosed after metastasis has already occurred, with the liver being the most frequently affected site. Both primary tumors and metastases have dense desmoplastic stroma due to a high percentage of fibroblasts within the tumor microenvironment (TME). Previously, we developed a tunable 3D biomimetic model of the liver metastatic niche (LMN) to investigate how local fibroblasts affect tumor growth and chemoresistance in PDAC liver metastasis. This study aims to investigate the contributions of fibroblasts at the primary versus metastatic sites. We used matched primary PDAC and liver metastatic (LM) organoids derived from the Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre (“KPC”) genetically engineered mouse model. This allows us to compare the effects of primary PDAC cancer associated fibroblasts (CAFs) and liver metastasis associated fibroblasts (MAFs) on tumor cell growth and chemoresistance. Rheometry analyses were conducted to study the impact of local fibroblasts on the extracellular matrix (ECM) stiffness. Our results showed that both storage and loss moduli were enhanced only when PDAC CAFs were present in the co-cultured gels compared to gels with MAFs. Additionally, the 3D biomimetic model showed fibroblasts increased tumor growth and chemoresistance to gemcitabine, only when they were derived from the same site as the tumor cells. This highlighted the importance of studying the organ-specific microenvironment to develop better treatment options for patients with metastatic PDAC. To delve deeper into the molecular basis of these observations, we conducted RNA-sequencing to identify and compare the gene expression profiles in primary and metastatic tumor organoids exposed to conditioned media from CAFs and MAFs using a transwell membrane co-culture model. Our results showed significant differences in gene expression based on the type of fibroblasts co-cultured with the organoids. Moreover, we investigated the role of MAF-derived exosomes on LM growth and chemoresistance using exosome depletion and direct exosome addition to LM organoids. Lastly, we performed exosomes size and distribution characterizations using dynamic light scattering (DLS) analysis. Taken together, these findings highlight the critical role of the organ-specific microenvironment in tumor progression and the necessity of targeted therapies to improve patient outcomes in metastatic PDAC. Our results underscore the importance of developing a tunable 3D biomimetic model of the LMN, as it enables the testing of novel therapeutic strategies designed to disrupt interactions between MAFs and tumor cells, and potentially advancing treatments for metastatic PDAC. Citation Format: Mahsa Pahlavanneshan, Weikun Xiao, Eileen Fung, Vaidhyanathan Mahaganapathy, Chae Young Eun, Chang-Il Hwang, Shannon Mumenthaler, Reginald Hill. Investigating the effects of fibroblasts derived from the primary versus the metastatic organ on 3D biomimetic models of pancreatic 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 A006.

Microplastics accumulated in breast cancer patients lead to mitophagy via ANXA2-mediated endocytosis and IL-17 signaling pathway

Breast cancer (BC) is the most common malignancy in women and the leading cause of cancer death. Microplastics (MPs) are plastic fragments with a diameter of less than 5 mm, easily ingested by organisms. Although MPs have been reported to enter the human body through diet, surgery, etc., whether MPs accumulate in BC and their effects have been largely unknown. Our study revealed a significant accumulation of MPs in BC patient samples. MPs pull-down experiments and mass spectrometry (MS) studies showed that MPs bound to annexin A2 (ANXA2) and were endocytosed into cells. This process resulted in mitochondrial damage and subsequent induction of mitophagy. Furthermore, after binding to ANXA2, MPs regulated mitophagy by inhibiting IL-17 exocytosis. These findings revealed the mechanism of toxic effects of MPs in patients with BC, clarified the molecular mechanism of ANXA2-IL-17 signaling pathway causing mitochondrial damage by MPs, and suggested the potential toxic effects and toxicological mechanisms of MPs.