Obesity-associated Cancer Research Articles

Targeting the menopause transition with metformin improves breast cancer outcomes, but discontinuation has deleterious effects on metabolic health: Findings from a preclinical model of postmenopausal breast cancer.

Women with obesity and/or type-II-diabetes have an increased breast cancer risk, increased metastasis, and poorer prognosis, especially after menopause. In a rat model of high-fat-diet and menopause-induced weight gain, we previously reported that treatment with the anti-diabetic drug metformin for 8-weeks after ovariectomy (OVX; modeling menopause) reduced growth of existing mammary tumors and inhibited new tumor formation. This identified the menopause transition as a potential window-of-opportunity for interventions to decrease obesity-associated breast cancer incidence and disease progression. Here, we extend these findings to determine if limiting metformin to the peak window of OVX-induced weight gain would have similar anti-cancer effects. Metformin during the first four weeks following OVX is critical to reducing tumor burden, as rats treated with metformin early (weeks0-4-postOVX) had reduced tumor burden. Conversely, initiating metformin later in the postOVX period (weeks 4-8postOVX) did not reduce cancer burden. Despite improved tumor outcomes, metformin withdrawal after the early postOVX time had detrimental metabolic effects, including weight gain and increased adiposity, insulin, IGF1, and HOMA-IR, which correlate with increased cancer risk. These data reveal early-postmenopause as a critical window when metformin decreases progression of existing disease and highlights the importance of maintaining treatment to prevent metabolic dysregulation, which could promote secondary tumors/metastasis. These findings also help explain the disconnect between epidemiological studies reporting anticancer benefits of metformin and more recent clinical trials that failed to see similar efficacy, potentially due to issues of timing and/or inclusion of women outside the early postmenopausal window and/or without underlying metabolic dysfunction.

The effects of muscle factors irisin on lipid metabolism in breast cancer: A possible mechanism anti-tumor mechanism of physical activity

Breast cancer is the most prevalent cancer in the female population and is a significant cause of global cancer deaths in this group. Obesity increases a woman’s risk of developing breast cancer and has a negative impact on prognosis. Metabolic alterations are an important part of the process of cancer migration; invasion and proliferation, with lipids being a major metabolic substrate for rapid cancer progression, capable of influencing the metabolic crosstalk between tumor cells and other cells in the tumor microenvironment. Physical activity-induced irisin affects the progression of obesity-associated breast cancer and is a new indicator for breast cancer diagnosis. Existing evidence suggests a potential inhibitory effect of physical activity-induced irisin on the progression of breast cancer. A strong association exists between obesity and breast cancer progression and outcomes. This paper discusses how physical activity-induced irisin may achieve cancer suppression by affecting lipid metabolic processes between breast cancer cells and cancer-associated adipocytes, and elucidates the molecular pathways involved in the effects of irisin on cancer lipid reprogramming, thereby helping to prevent the metastatic progression of breast cancer, and ultimately improving the survival rate of this patient group.

Novel perspectives on the link between obesity and cancer risk: from mechanisms to clinical implications.

Existing epidemiologic and clinical studies have demonstrated that obesity is associated with the risk of a variety of cancers. In recent years, an increasing number of experimental and clinical studies have unraveled the complex relationship between obesity and cancer risk and the underlying mechanisms. Obesity-induced abnormalities in immunity and biochemical metabolism, including chronic inflammation, hormonal disorders, dysregulation of adipokines, and microbial dysbiosis, may be important contributors to cancer development and progression. These contributors play different roles in cancer development and progression at different sites. Lifestyle changes, weight loss medications, and bariatric surgery are key approaches for weight-centered, obesity-related cancer prevention. Treatment of obesity-related inflammation and hormonal or metabolic dysregulation with medications has also shown promise in preventing obesity-related cancers. In this review, we summarize the mechanisms through which obesity affects the risk of cancer at different sites and explore intervention strategies for the prevention of obesity-associated cancers, concluding with unresolved questions and future directions regarding the link between obesity and cancer. The aim is to provide valuable theoretical foundations and insights for the in-depth exploration of the complex relationship between obesity and cancer risk and its clinical applications.

The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity.

Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell-derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.

Overweight and Obesity-Associated Gastric Cancer Among Non-Asians.

Overweight and Obesity-Associated Gastric Cancer Among Non-Asians.

Single-cell RNA-sequencing reveals a unique landscape of the tumor microenvironment in obesity-associated breast cancer

As two diseases with rapidly increasing incidence, the molecular linkages between obesity and breast cancer (BC) are intriguing. Overall, obesity may be a negative prognostic factor for BC. Single-cell RNA-sequencing (scRNA-seq) was performed on tumor tissues from 6 obese and non-obese BC patients. With 48,033 cells analyzed, we found heterogeneous tumor epithelium and microenvironment in these obese and lean BC patients. Interestingly, the obesity-associated epithelial cells exhibited specific expression signatures which linked tumor growth and hormone metabolism in BC. Notably, one population of obesity-specific macrophage up-regulated the nuclear receptor subfamily 1 group H member 3 (NR1H3), which acted a transcription factor and regulated FABP4 expression through its interaction with the DNA of SREBP1, and further increased the proliferation of tumor cells in BC. Using single-cell signatures, our study illustrate cell diversity and transcriptomic differences in tumors from obese and non-obese BC patients, and sheds light on potential molecular link between lipid metabolism and BC.

Obesity-Associated Colorectal Cancer.

Colorectal cancer (CRC) affects approximately 2 million people worldwide. Obesity is the major risk factor for CRC. In addition, obesity contributes to a chronic inflammatory stage that enhances tumor progression through the secretion of proinflammatory cytokines. In addition to an increased inflammatory response, obesity-associated cancer presents accrued molecular factors related to cancer characteristics, such as genome instability, sustained cell proliferation, telomere dysfunctions, angiogenesis, and microbial alteration, among others. Despite the evidence accumulated over the last few years, the treatments for obesity-associated CRC do not differ from the CRC treatments in normal-weight individuals. In this review, we summarize the current knowledge on obesity-associated cancer, including its epidemiology, risk factors, molecular factors, and current treatments. Finally, we enumerate possible new therapeutic targets that may improve the conditions of obese CRC patients. Obesity is key for the development of CRC, and treatments resulting in the reversal of obesity should be considered as a strategy for improving antineoplastic CRC therapies.

Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes

Thirteen human malignant neoplasms have been identified as obesity-associated cancers (OACs), ie, the presence of excess body fat is associated with increased risk of developing cancer and worse prognosis in patients with these specific tumors. The glucagon-like peptide receptor agonist (GLP-1RA) class of pharmaceuticals are effective agents for the treatment of type 2 diabetes (T2D) and for achieving weight loss, but the association of GLP-1RAs with the incident risk of 13 OACs is unclear. To compare the incident risk of each of the 13 OACs in patients with T2D who were prescribed GLP-1RAs vs insulins or metformin. This retrospective cohort study was based on a nationwide multicenter database of electronic health records (EHRs) of 113 million US patients. The study population included 1 651 452 patients with T2D who had no prior diagnosis of OACs and were prescribed GLP-1RAs, insulins, or metformin during March 2005 to November 2018. Data analysis was conducted on April 26, 2024. Prescription of GLP-1RAs, insulins, or metformin. Incident (first-time) diagnosis of each of the 13 OACs occurring during a 15-year follow-up after the exposure was examined using Cox proportional hazard and Kaplan-Meier survival analyses with censoring applied. Hazard ratios (HRs), cumulative incidences, and 95% CIs were calculated. All models were adjusted for confounders at baseline by propensity-score matching baseline covariates. In the study population of 1 651 452 patients with T2D (mean [SD] age, 59.8 [15.1] years; 827 873 [50.1%] male and 775 687 [47.0%] female participants; 5780 [0.4%] American Indian or Alaska Native, 65 893 [4.0%] Asian, 281 242 [17.0%] Black, 13 707 [0.8%] Native Hawaiian or Other Pacific Islander, and 1 000 780 [60.6%] White participants), GLP-1RAs compared with insulin were associated with a significant risk reduction in 10 of 13 OACs, including in gallbladder cancer (HR, 0.35; 95% CI, 0.15-0.83), meningioma (HR, 0.37; 95% CI, 0.18-0.74), pancreatic cancer (HR, 0.41; 95% CI, 0.33-0.50), hepatocellular carcinoma (HR, 0.47; 95% CI, 0.36-0.61), ovarian cancer (HR, 0.52; 95% CI, 0.03-0.74), colorectal cancer (HR, 0.54; 95% CI, 0.46-0.64), multiple myeloma (HR, 0.59; 95% CI, 0.44-0.77), esophageal cancer (HR, 0.60; 95% CI, 0.42-0.86), endometrial cancer (HR, 0.74; 95% CI, 0.60-0.91), and kidney cancer (HR, 0.76; 95% CI, 0.64-0.91). Although not statistically significant, the HR for stomach cancer was less than 1 among patients who took GLP-1RAs compared with those who took insulin (HR, 0.73; 95% CI, 0.51-1.03). GLP-1RAs were not associated with a reduced risk of postmenopausal breast cancer or thyroid cancer. Of those cancers that showed a decreased risk among patients taking GLP-1RAs compared with those taking insulin, HRs for patients taking GLP-1RAs vs those taking metformin for colorectal and gallbladder cancer were less than 1, but the risk reduction was not statistically significant. Compared with metformin, GLP-1RAs were not associated with a decreased risk of any cancers, but were associated with an increased risk of kidney cancer (HR, 1.54; 95% CI, 1.27-1.87). In this study, GLP-1RAs were associated with lower risks of specific types of OACs compared with insulins or metformin in patients with T2D. These findings provide preliminary evidence of the potential benefit of GLP-1RAs for cancer prevention in high-risk populations and support further preclinical and clinical studies for the prevention of certain OACs.

Severe obesity is associated with worse outcomes than lean metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in people with obesity. We aimed to study the association of body mass index (BMI) with clinical outcomes in patients with MASLD. A retrospective cohort of 32,900 patients with MASLD, identified through the International Classification of Diseases-9 and 10 codes within the electronic health records of a large US-based health system, with a mean follow-up of 5.5 years (range: 1-15y), was stratified into 6 BMI categories, <25, 25-<30, 30-<40, 40-<50, and ≥50kg/m2. The risk of liver decompensation and extrahepatic obesity-associated cancers had a J-shaped profile (both ps for linear and quadratic terms <0.05). Compared to patients with BMI 25-<30kg/m2, the adjusted HRs (95% CIs) for liver decompensation of patients with BMI <25 and BMI ≥50kg/m2 were 1.44 (1.17-1.77) and 2.27 (1.66-3.00), respectively. The corresponding figures for obesity-associated extrahepatic cancer were 1.15 (0.97-1.36) and 1.29 (1.00-1.76). There was an inverse association for BMI with liver transplantation and non-obesity-associated cancer (both ps for linear terms <0.05), but no association with HCC or all types of cancers combined. A similar J-shaped association between BMI and all-cause mortality was observed; adjusted HRs (95% CIs) for BMI <25 and ≥50kg/m2 were 1.51 (1.32-1.72) and 3.24 (2.67-3.83), respectively, compared with BMI 25-<30kg/m2 (both ps for linear and quadratic terms <0.001). Patients with MASLD and very severe obesity (BMI ≥50kg/m2) had the highest risk, exceeding that of patients with lean MASLD, for developing liver decompensation, obesity-associated extrahepatic cancers, or dying from any cause.

Metabolic Dysregulation and Cancer Risk Program (MeDOC): a transdisciplinary approach to obesity-associated cancers.

With the escalating prevalence of obesity, the association between obesity and cancer is a growing public health concern. Obesity will soon surpass tobacco smoking as the most important preventable cause of cancer. Obesity-driven mechanisms can alter cell functions to induce metabolic changes, chronic inflammation, and insulin resistance that are believed to contribute to cancer risk and development; yet the specific underlying biological mechanisms of obesity-related cancer development are largely unknown. The Metabolic Dysregulation and Cancer Risk Program: a transdisciplinary approach to obesity-associated cancers (MeDOC) is a trans-National Cancer Institute research initiative supported by the Division of Cancer Control and Population Sciences, the Division of Cancer Biology, the Division of Cancer Prevention, and the Center to Reduce Cancer Health Disparities. The overall purpose of the MeDOC Program is to advance our understanding of the underlying mechanisms that connect obesity, metabolic dysregulation, and increased obesity cancer risk as well as identify markers that will enhance cancer risk prediction, improve screening for high-risk individuals, and identify targets for preventive and therapeutic interventions for cancer interception or treatment. This report describes the funded research projects, the Coordinating Center, and the goals of the MeDOC program.

The relationship between cardiometabolic abnormalities and mortality among women with and without cancer in the Women’s Health Initiative (WHI).

e24007 Background: Prior studies of women with obesity-associated cancers in the Women’s Health Initiative (WHI) showed higher overall and mortality due to cardiovascular disease (CVD) for women with a higher number of cardiometabolic risk factors at baseline. It is unclear if this risk differs from women without cancer. In order to determine if this relationship differs among both groups, we compared the association between cardiometabolic risk factors and mortality among women in the WHI with and without cancer. Methods: Women with one of five early-stage obesity-associated cancers (breast, colorectal, endometrial, ovarian, non-Hodgkin lymphoma), and matched controls without history of cancer, were selected from the WHI-Life and Longevity After Cancer (LILAC) study. Cardiometabolic risk factors included high waist circumference (WC) (≥88 cm), systemic hypertension ( &gt; 130/85 mm Hg) measured at study visits, and self-reported history of diabetes and elevated cholesterol. Multivariable Cox proportional hazards models (all-cause mortality) and Fine-Gray models (CVD and non-CVD mortality) were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to evaluate the association between baseline cardiometabolic risk factors and survival outcomes for the cancer and non-cancer cohorts in separate models. Sensitivity analyses included women in the cancer-cohort who received cardiotoxic chemotherapy. Results: A total of 7,491 and 35,508 women were analyzed in the cancer and non-cancer cohorts respectively. CVD was the most common cause of death (excluding cancer) in both non-cancer (41.4%) and cancer (41.5%) cohorts. Adjusted Cox models showed that the proportion of deaths due to any cause, by number of cardiometabolic risk factors, was significantly higher in the non-cancer compared to the cancer cohort (p-value = 0.02), with the HR values being higher for those with 3-4 risk factors compared to 1-2. Similar results were seen for each individual risk factor except for WC. Regarding CVD and non-CVD mortality, in competing risks models, there were no significant differences in the risk of death by number of risk factors, between the cancer and non-cancer cohorts (p = 0.21 and 0.22) respectively. Sensitivity analyses for women who received a cardiotoxic regimen, (81.5% anthracyclines alone, 13.4% anti-HER2 alone, and 5.1% both) showed no differences in the results for all-cause mortality, and CVD mortality. However, for non-CVD mortality, the proportion of deaths was significantly higher for women in the non-cancer cohort (p = 0.03). Conclusions: Cardiometabolic risk factors had a greater impact on mortality among women without cancer compared to those with cancer, except for death due to CVD which was similar between groups, suggesting that CVD risk reducing interventions are of equal importance for women with and without cancer.

Comparative risk of obesity-related cancer with glucagon-like protein-1 receptor agonists vs. bariatric surgery in patients with BMI ≥ 35.

10508 Background: Bariatric surgery is suggested to reduce the risk of obesity-related cancers, prompting us to explore whether glucagon-like peptide-1 receptor agonist (GLP-1 RA) offers a similar association. Methods: We queried TriNetX, a global healthcare database to identify patients with BMI of ≥ 35. Three pair-wise propensity score-matched (PSM) comparisons were created: 1) GLP-1 RA vs. Bariatric Surgery, 2) GLP-1 RA vs. No Intervention, 3) Bariatric Surgery vs. No Intervention. Cohorts were exclusive and no intervention was defined as an ambulatory visit. Patients required a minimum of 1 year of continuous GLP-1 RA therapy or follow-up, extended to 3 and 5 years in sensitivity analyses. Exclusions included a history of cancer or in situ neoplasms, as well as factors that significantly impact cancer risk and/or mortality including alcohol use disorder, organ transplantation, HIV, decompensated cirrhosis, peptic ulcer disease, dialysis dependency, left ventricular ejection fraction ≤ 20%, or other weight loss medication exposure. PSM utilized obesity therapy indications, Elixhauser and Charlson Comorbidity indices, prior follow-up, and demographics. Follow-up extended to 15 years, assessing 13 obesity-related cancers after intervention using Kaplan Meier (KM) and Cox-proportional Hazards Models (HR). Secondary outcomes included the risk of all-cause mortality and precancerous lesions. Results: After PSM, we identified 20,009, 3,229, and 11,104 patients in Comparison 1, 2, and 3, respectively. For Comparison 1, at 15 years, 273 (KM event rate 8.75%) patients on GLP-1 RA therapy and 397 (6.58%) with bariatric surgery developed an obesity-associated cancer, respectively (HR 0.99; 95% CI 0.87 - 1.13). Patients who received GLP-1 RA (HR 0.61; 95% CI 0.46 - 0.81) and bariatric surgery (HR 0.78; 95% CI 0.67 - 0.91) had a reduced risk of obesity-related cancer compared to no intervention. Among 20,009 patients, 40 (0.353%) and 61 (0.876%) of patients developed thyroid cancer in the GLP-1 RA and bariatric surgery groups, respectively (HR: 0.837; CI: 0.558 - 1.254). Patients lost significantly more weight after bariatric surgery as compared to GLP-1 RA at 1-2 years (BMI change -5.31 ± 6.05 vs. -1.57 ± 5.12 kg/m2; p &lt; 0.0001). GLP-1 RA initiation was associated with lower all-cause mortality compared to control (HR 0.5; 95% CI 0.40 - 0.62) and bariatric surgery (HR 0.859; 95% CI 0.77 - 0.96). Neither GLP-1 RA nor bariatric surgery was associated with precancerous lesions compared to control. Sensitivity analyses supported the above outcomes. Conclusions: GLP-1 RA was associated with a lower risk of obesity-related cancer comparable to bariatric surgery in patients with BMI ≥ 35. GLP-1 RA has superior all-cause mortality benefits despite inferior weight loss compared to bariatric surgery.

Physical Activity Decreases Inflammation and Delays the Development of Obesity-Associated Pancreatic Ductal Adenocarcinoma.

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity represent a potential approach to prevent obesity-associated PDAC. In this study, we examined whether decreasing obesity through physical activity (PA) and/or dietary changes could decrease inflammation in humans and prevent obesity-associated PDAC in mice. Comparison of circulating inflammatory-associated cytokines in subjects (overweight and obese) before and after a PA intervention revealed PA lowered systemic inflammatory cytokines. Mice with pancreatic-specific inducible KrasG12D expression were exposed to PA and/or dietary interventions during and after obesity-associated cancer initiation. In mice with concurrent diet-induced obesity and KrasG12D expression, the PA intervention led to lower weight gain, suppressed systemic inflammation, delayed tumor progression, and decreased proinflammatory signals in the adipose tissue. However, these benefits were not as evident when obesity preceded pancreatic KrasG12D expression. Combining PA with diet-induced weight loss (DI-WL) delayed obesity-associated PDAC progression in the genetically engineered mouse model, but neither PA alone nor combined with DI-WL or chemotherapy prevented PDAC tumor growth in orthotopic PDAC models regardless of obesity status. PA led to the upregulation of Il15ra in adipose tissue. Adipose-specific overexpression of Il15 slowed PDAC growth but only in nonobese mice. Overall, our study suggests that PA alone or combined with DI-WL can reduce inflammation and delay obesity-associated PDAC development or progression. Lifestyle interventions that prevent or manage obesity or therapies that target weight loss-related molecular pathways could prevent progression of PDAC. Significance: Physical activity reduces inflammation and induces changes to adipose-related signaling to suppress pancreatic cancer, supporting the potential of obesity management strategies to reduce the risk of developing pancreatic cancer. See related commentary by Sogunro and Muzumdar, p. 2935.

The Burden of Overweight and Obesity-Associated Gastrointestinal Cancers in Low and Lower-Middle-Income Countries: A Global Burden of Disease 2019 Analysis.

Obesity is associated with cancer, including gastrointestinal (GI). Data from low (LICs) and lower-middle-income countries (MICs) are limited. We utilized data from the Global Burden of Disease Study 2019 to determine the mortality from GI cancer risk of high body mass index (BMI) in these countries. Mortality rates of GI cancers from high BMI increased in LICs and lower MICs, while burdens decreased or remained stable in high and middle-income countries. The GI cancer-related burden from high BMI increased in LICs and lower MICs, necessitating a concerted effort to tackle the obesity pandemic.

MiRNAs as Interconnectors between Obesity and Cancer.

Obesity and cancer are a concern of global interest. It is proven that obesity may trigger the development or progression of some types of cancer; however, the connection by non-coding RNAs has not been totally explored. In the present review, we discuss miRNAs and lncRNAs dysregulation involved in obesity and some cancers, shedding light on how these conditions may exacerbate one another through the dysregulation of ncRNAs. lncRNAs have been reported as regulating microRNAs. An in silico investigation of lncRNA and miRNA interplay is presented. Our investigation revealed 44 upregulated and 49 downregulated lncRNAs in obesity and cancer, respectively. miR-375, miR-494-3p, miR-1908, and miR-196 were found interacting with 1, 4, 4 and 4 lncRNAs, respectively, which are involved in PPARγ cell signaling regulation. Additionally, miR-130 was found to be downregulated in obesity and reported as modulating 5 lncRNAs controlling PPARγ cell signaling. Similarly, miR-128-3p and miR-143 were found to be downregulated in obesity and cancer, interacting with 5 and 4 lncRNAs, respectively, associated with MAPK cell signaling modulation. The delicate balance between miRNA and lncRNA expression emerges as a critical determinant in the development of obesity-associated cancers, presenting these molecules as promising biomarkers. However, additional and deeper studies are needed to reach solid conclusions about obesity and cancer connection by ncRNAs.

Abstract 3935: Involvement of nanoscale physical communication in obesity-associated breast cancer severity

Abstract Obesity is a risk factor for several cancers, including breast cancer, and contributes up to 20% of cancer-related deaths. Growing evidence from both clinical and preclinical studies indicates that increased obesity is associated with increases in cancer incidence, progression, metastasis, and therapeutic resistance. According to the Centers for Disease Control and Prevention (CDC), more than 70% and 40% of American adults can be classified as overweight and obese, respectively. However, treatment strategies for dealing with cancer in obese patients have not advanced apart from lifestyle interventions. However, several signaling mechanisms have been proposed related to the inflammatory and metabolic impact of obese adipocytes in promoting cancer progression. However, a lack of mechanistic understanding led to no specific treatment strategies have been proposed which can specifically downregulate the key regulator by which obese adipocytes promote cancer progression. Thus, translational research initiatives are immediately needed to provide mechanistic justifications for these striking statistics in order to better serve this growing segment of the population. Here, we have shown the role of nanoscale physical communication between breast cancer cells and adipose tissue in promoting cancer progression. Using high-resolution optical and electron microscopy, we have found that breast cancer cells form nanoscale tubular communications with obese adipocytes. Moreover, the cancer cells hijack mitochondria from obese adipocytes. However, coculturing cancer cells and obese adipocytes in the Boyden chamber, allowing exosomal and paracrine communication but blocking direct physical communication, revealed negligible mitochondria transfer. This observation indicates an active transfer of mitochondria via nanotube. A significantly higher rate of mitochondria transfer from obese adipocytes to cancer cells has been observed than non-differentiated pre-adipocytes. The transfer of mitochondria results in an increase in the metabolism of the cancer cells. The mechanistic investigation of the nanotube formation revealed actin's presence as the major component in the nanotube. The exocyst-GTPase protein complex has a prime contribution in actin remodeling and nanotube formation. Inhibition of exocyst-GTPase using a pharmacological inhibitor results in a significant reduction in nanotube-mediated mitochondria transfer. Conclusion: Our goal is to (i) investigate the direct physical connection between adipocytes and cancer cells and the effect on cancer progression and (ii) eliminate mortality related to obesity-associated breast cancer severity by introducing a new therapeutic strategy. Here, we have shown how cancer cells communicate with obese adipocytes and receive additional metabolic power for proliferation. The in vivo investigation of the same is under progress. Citation Format: Tanmoy Saha, Balaaji Baanupriya Srinivasan, Shiladitya Sengupta. Involvement of nanoscale physical communication in obesity-associated breast cancer severity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3935.

Abstract 2452: Clinical importance of nicotinamide nucleotide transhydrogenase in obesity-associated colorectal cancer

Abstract Background: Obesity is increasing worldwide, and many associated diseases are emerging as global health problems. There is a relationship between body mass and the risk of developing colorectal cancer (CRC). However, predictive biomarkers of survival with body mass remain elusive. Therefore, we aimed to identify novel clinically relevant biomarkers for obesity-associated CRC. Methods: We searched for biomarker candidates in The Cancer Genome Atlas CRC cohort. We divided the TCGA CRC cohort (n=268) data into 3 groups (healthy weight CRC group [HT], adjacent normal tissue from the HT group [AN]), and obesity CRC group [OT]). Candidates were validated by survival analysis after immunohistochemistry in an independent cohort of 420 patients. Results: The gene expression levels of NNT, PANK3, PPARGC1B, RTL6, FAM220A, and TMEM9 were associated with survival in overweight and obese patients with CRC from TCGA cohort. These findings were validated using protein expression data from our independent cohort. In our patient cohort, the hazard ratio (HR) of the subgroup of low NNT versus that of high NNT in terms of 5-year event-free survival (EFS) was 2.20 (adjusted for age and sex, 95% CI: 1.01-4.80, p &amp;lt; 0.05) among patients of obesity-associated CRC. When both TNM staging and NNT expression were considered, patients of obesity-associated CRC with low NNT expression and advanced stage III-IV cancer had a HR of 21.20 (adjusted for age and sex, 95% CI: 2.88-156.08, p &amp;lt; 0.01) compared to those with high NNT expression and early stage I-II cancer. However, when patients of obesity-associated CRC with high NNT expression and advanced stage III-IV cancer were compared to those with high NNT expression and early stage I-II cancer, the former subgroup had a HR of 8.39 (adjusted for age and sex, 95% CI: 1.03-68.39, p &amp;lt; 0.05) in terms of the 5-year EFS. Finally, when the 5-year disease-specific survival analysis was performed, the patients of obesity-associated CRC with low NNT expression and advanced stage III-IV cancer were found to have a HR of 14.05 (adjusted for age and sex, 95% CI: 1.89-104.38, P = 0.01) compared to those with high NNT expression and early stage I-II cancer. Furthermore, low NNT expression results in the inactivation of several metabolic pathways, including ROS-related pathways. Conclusions: NNT is a novel and promising CRC prognostic biomarker for overweight and obese patients. It can provide clinicians with early indicators of patient prognosis and aid in appropriate treatment selection. Citation Format: Soyeon Jeong, Sungjin Park, Jungsuk An, Myunghee Kang, Seungyoon Nam, Jung Ho Kim. Clinical importance of nicotinamide nucleotide transhydrogenase in obesity-associated colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2452.

Abstract 7459: iNOS inhibition through L-NMMA reveals immunostimulatory effects in obesity-associated triple-negative breast cancer (TNBC) tumors

Abstract Purpose of study: This study examines how obesity, an inflammatory condition, impacts treatment outcomes in triple-negative breast cancer (TNBC). Obesity fosters an unfavorable tumor microenvironment (TME) marked by immune suppression, metabolic shifts, and protumoral cytokine release. Elevated nitric oxide (NO) levels linked with obesity compromise vascular integrity, promoting breast cancer metastasis. This study examines whether combining standard chemotherapy (docetaxel) with NOS inhibition via L-NMMA could reshape the TME and bolster antitumor effects in TNBC within an obese mouse model. Experimental Procedure: C57bl/6 mice, a TNBC syngeneic mouse model, were fed a high-fat diet (HFD) or normal diet (ND) for 10 weeks. Tumors were induced orthotopically via E0771 cell line injection into the mammary fat pad. Upon reaching 100 mm^3, mice were randomized into vehicle and L-NMMA treatment groups. Digital spatial transcriptomics using NanoString™ GeoMx and nCounter platforms were conducted on FFPE tumor tissue sections from ND, HFD, and HFD+LNMMA treated mice. A panel targeting 64 protein markers aided in immune cell phenotyping and TME assessment. Results: HFD-induced tumors exhibited increased growth, elevated pro-inflammatory cytokine levels, and heightened iNOS expression. Unsupervised hierarchical clustering after nCounter analysis revealed a distinct protein expression signature in HFD tumors associated with T cell infiltration and exhaustion, as evidenced by the upregulation of CD3, CD4, PD-1/PD-L1, FOXP3, and CTLA 4. Markers for identifying immunosuppressed macrophages (F4/80 and CD163) were also elevated. Remarkably, LNMMA treatment on HFD tumors led to reduced tumor growth and lower expression levels of these markers, alongside a downregulation of survival/proliferation markers such as p53, Ki67, and key members of the Pi3k signaling pathway such as phospoAktSer473. Conclusions: Our findings indicate a distinct immunomodulatory mechanism of iNOS inhibition in HFD tumors, which displayed expression profiles marked by heightened immunosuppressive markers when compared to ND tumors. LNMMA treatment reversed this phenotype, aligning the profile closer to ND tumors. These discoveries underscore the potential of inhibiting iNOS to reshape the immune tumor microenvironment (TME) and modulate pathways linked to cell proliferation and survival. This presents a promising avenue for enhancing the effectiveness of treatments for triple-negative breast cancer (TNBC). Citation Format: Ivonne Uzair, Kai Sun, Seun Hynes, Wei Qian, Jianying Zhou, Karina Ortega Martinez, Liliana Guzman, Polina Matre, Jenny Chang. iNOS inhibition through L-NMMA reveals immunostimulatory effects in obesity-associated triple-negative breast cancer (TNBC) tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7459.

Abstract 1519: Effect of obesity on CD4+ T cells in the tumor immune microenvironment of colorectal cancer

Abstract Background: The number of new cases and deaths from colorectal cancer (CRC) is increasing rapidly, and obesity is considered one of the risk factors. Obesity-associated cancers are related to the overproduction of hormones, induction of reactive oxygen species (ROS) production by free fatty acids, and changes in the gut microbiome. Obesity also promotes immune cell dysfunction in the tumor immune microenvironment (TIME). The increase of fatty acid levels due to obesity causes metabolic reprogramming and decreases the cytotoxic activity of natural killer (NK) cells and CD8+ T cells, which accelerate tumor progression. However, the impact of obesity on CD4+ T cells in the TIME remains unclear. Therefore, this study aimed to clarify how obesity affected the number and the anti-tumor activity of CD4+ T cells in CRC using mouse models. Methods: Seven-week-old male C57BL/6J mice were randomly divided into two groups and fed the control diet (CD) or high-fat diet (HFD) for nine weeks. Blood samples were collected from the buccal vein of the mice every four weeks after feeding for analysis. MC38 CRC cells of 4 × 106 were subcutaneously inoculated in the middle of the backs of mice to analyze tumor progression. Three weeks after tumor cell inoculation, the mice were sacrificed, and the immune cells of the tumor, blood, and various organs were analyzed. Results: After nine weeks of feeding, the HFD-fed mice had a significantly increased body weight compared to CD-fed mice. Flow cytometry results revealed that the number and frequency of CD4+ T cells in the blood were significantly reduced in HFD-fed mice compared to those in CD-fed mice, and the expression of programmed death-1 (PD-1) in CD4+ T cells in HFD-fed mice was significantly higher than that in CD-fed mice at eight weeks. Three weeks after tumor inoculation, HFD feeding accelerated tumor growth and decreased the survival rate. The number of CD4+ T cells in the tumors was significantly reduced in HFD-fed mice compared to that in CD-fed mice (55.9 vs 18.2 cells/mg; 95% CI 14.9-60.3 cells/mg; P = 0.006). The number of CD8+ T cells in the tumors was also reduced, which was more pronounced for CD4+ T cells than for CD8+ T cells. In addition, the production of cytokines such as IFN-γ and TNF-α was significantly reduced in CD4+ T cells and CD8+ T cells of HFD-fed mice. In a depletion analysis of CD4+ T cells, the feeding-dependent acceleration of tumor growth was not observed in each group. This result indicated that CD4+ T cells were involved in accelerating tumor growth due to HFD-induced obesity. Conclusion: We showed that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells, ultimately accelerating the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity. Citation Format: Masayuki Ando, Kota Yamada, Masafumi Saito, Kimihiro Yamashita, Takao Tsuneki, Yuri Adachi, Tomoki Abe, Tomosuke Mukoyama, Ryuichiro Sawada, Yasufumi Koterazawa, Hitoshi Harada, Naoki Urakawa, Hironobu Goto, Hiroshi Hasegawa, Shingo Kanaji, Takeru Matsuda, Yoshihiro Kakeji. Effect of obesity on CD4+ T cells in the tumor immune microenvironment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1519.

Abstract 2188: Tirzepatide treatment restores antitumor immunity in a model of obesity-driven cancer

Abstract Obesity is a widely and increasingly prevalent disease and a risk factor for several cancers. Recent work has shown that weight loss following bariatric surgery is potently protective against obesity-associated cancers. However, little is known about the potential anticancer effects of weight loss achieved through incretin-based therapies. We therefore interrogated the effects of the dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist tirzepatide (TZP) on body weight and tumor progression in a mouse model of obesity and transplanted colon cancer cells. Moreover, we tested whether TZP-mediated weight loss can reverse obesity-associated suppression of CD8+ T cell immunity. Male C57BL/6J mice were fed either 60 kcal% fat diet (D12492) or a sucrose-matched 10 kcal% fat diet (D12450J) for ≥15 weeks to generate diet induced obese (DIO) or control mice, respectively. Once DIO mice reached a body weight of 47 g they were randomized to begin TZP treatment or receive a vehicle control every other day for 3 weeks (when stable body weights were reached for TZP mice). All mice then received subcutaneous injections with 2.5 × 105 MC38 cells and continued to receive TZP or vehicle. To determine the role of CD8+ T cell mediated tumor control in driving the effects of TZP treatment, mice received either CD8-depleting antibodies or an isotype control at days -2, 0, 2 relative to tumor cell injection and subsequently every 4 days. Tumor mass was determined by digital scale. Fasting blood glucose, body weight loss, and body composition were monitored to determine the metabolic effects of TZP. Immune cell populations were measured by full spectrum flow cytometry. We found TZP reduced body weight, fasting blood glucose, and adiposity relative to DIO mice, as was expected. These metabolic improvements were accompanied by reduction of tumor mass in TZP mice relative to DIO mice. DIO mice had increased levels of exhausted T cells which were normalized by TZP treatment. Depletion of CD8+ cells did not alter the tumor mass of DIO mice, indicating negligible CD8+ T cell-mediated tumor control. In contrast, CD8+ cell depletion in control and TZP mice increased in tumor masses to the levels comparable to those of DIO mice. These results demonstrate that TZP can mitigate obesity-associated acceleration of tumor growth and restore markers of effective antitumor T cell immunity. Critically, we find that restoration of CD8+ T cell function is essential for TZP’s ability to limit tumor growth in DIO mice. Taken together, these results demonstrate that the metabolic improvements achieved by TZP treatment are accompanied by mitigation of obesity-driven immunosuppression. These findings shed important light on the potential for TZP and other incretin-based therapies to limit obesity-associated cancer progression, and are especially timely given the growing population of patients utilizing incretin-based therapies. Citation Format: Michael F. Coleman, Elaine M. Glenny, Tori L. McFarlane, Hannah M. Malian, Claire E. Gates, Fangxin Chen, Alyssa N. Ho, Violet A. Kiesel, Stephen D. Hursting. Tirzepatide treatment restores antitumor immunity in a model of obesity-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2188.