American Association for Cancer Research
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Supplementary Figures S1 - S15 from Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy

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journal contribution
posted on 2023-04-03, 21:03 authored by Joao Incio, Hao Liu, Priya Suboj, Shan M. Chin, Ivy X. Chen, Matthias Pinter, Mei R. Ng, Hadi T. Nia, Jelena Grahovac, Shannon Kao, Suboj Babykutty, Yuhui Huang, Keehoon Jung, Nuh N. Rahbari, Xiaoxing Han, Vikash P. Chauhan, John D. Martin, Julia Kahn, Peigen Huang, Vikram Desphande, James Michaelson, Theodoros P. Michelakos, Cristina R. Ferrone, Raquel Soares, Yves Boucher, Dai Fukumura, Rakesh K. Jain

Supplementary Figures S1 - S15. Supplementary Figure S1. Effect of obesity on tumor initiation. Supplementary Figure S2. Adipose tissue - tumor interaction. Supplementary Figure S3. Correlation of collagen-I levels with tumor size, co-expression of collagen-I and hyaluronan in PSCs, and impact of obesity on desmoplasia and tumor hyaluronan levels. Supplementary Figure S4. Additional Western blotting data from PAN02 tumors. Supplementary Figure S5. Additional effects of AT-1 inhibition on obesity-aggravated desmoplasia, perfusion and drug delivery. Supplementary Figure S6. Additional data on the effect of obesity on immune cell infiltration in tumors. Supplementary Figure S7. Effects of TAN depletion on vessel perfusion in obese mice. Supplementary Figure S8. Effect of obesity on cytokine profile in AK4.4 tumors. Supplementary Figure S9. Effects of TAN depletion on tumor cytokine expression in obese mice. Supplementary Figure S10. Additional effects of losartan on the tumor immune microenvironment. Supplementary Figure S11. Distribution of PDAC patients according to their BMI. Supplementary Figure S12. Effect of obesity on the expression of AT1, Ly6g, and AT1/Ly6g double positivity in PAN02 tumors. Supplementary Figure S13. Representative picture of AT1 expression in cancer-associated adipocytes (arrows) in PAN02 tumors. Supplementary Figure S14. Additional effects of AT1 inhibition on obesity-aggravated microenvironment. Supplementary Figure S15. Prevalance of hypertesion in PDAC patients.



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It remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.Significance: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852–69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821.This article is highlighted in the In This Issue feature, p. 803