Jad Belle
Program: Molecular Genetics and Genomics
Current advisor: David G. DeNardo, PhD
Undergraduate university: McGill University
Research summary
Pancreatic Ductal Adenocarcinoma (PDAC) is the most lethal solid malignancy with a 12% 5-year survival rate. Most tumors are detected at metastatic stages that are extremely resistant to therapy. PDAC recalcitrance is driven by a unique tumor microenvironment (TME) comprising dense collagenous fibrosis embedded with an abundance of cancer associated fibroblasts (CAFs) and infiltrating leukocytes. Preclinical studies have indicated that PDAC CAFs can have both pro- and anti-tumorigenic effects. This is likely owed to CAF phenotypic heterogeneity which was recently uncovered by single cell transcriptomics. Three major CAF subpopulations have been identified in mouse and human PDAC thus far: myofibroblastic (myCAF), inflammatory (iCAF), and antigen presenting (apCAF). However, the specific impact and phenotypic drivers of CAF heterogeneity in PDAC remain to be determined.
Senescent CAFs have been shown to regulate fibrosis and anti-tumor immunity in skin and liver cancer models. These influences on the TME are mediated by a senescence-associated secretory phenotype (SASP) which comprises context-specific matrix and immune modulatory factors. My thesis work aimed to identify a putative senescent CAF population in PDAC and determine its impact on the TME.
We found that a subpopulation of senescent myCAFs (SenCAFs) localize near tumors ducts and accumulate with PDAC progression. We demonstrated that senescent pancreatic fibroblasts are pro-tumorigenic in transplantable PDAC models through a partially T cell dependent mechanism. To assess the impact of senescent CAFs in spontaneous PDAC, we crossed the KPPC genetic model of PDAC (LSL-KRAS[G12D];p53[fl/fl];Pdx1-CRE) with the INK-ATTAC (p16/INK4a Apoptosis Through Targeted Activation of Caspase) senescent cell depletion model. Senescence depletion with the KPPC-IA model or the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Our findings demonstrate that SenCAFs promote PDAC progression, fibrosis, and immune cell dysfunction. Modulating CAF senescence could be utilized clinically to shape a more permissive PDAC microenvironment that enhances immunotherapy efficacy.
Graduate publications
Ye J, Baer JM, Faget DV, Morikis VA, Ren Q, Melam A, Delgado AP, Luo X, Mullick Bagchi S, Belle JI, Campos E, Friedman M, Veis DJ, Knudsen ES, Witkiewicz AK, Powers S, Longmore GD, DeNardo DG, Stewart SA. 2024 Senescent CAFs mediate immunosuppression and drive breast cancer progression. Cancer Discov, 14(7):1302-23.
Belle JI, Sen D, Baer JM, Liu X, Lander VE, Ye J, Sells BE, Knolhoff BL, Faiz A, Kang LI, Qian G, Fields RC, Ding L, Kim H, Provenzano PP, Stewart SA, DeNardo DG. 2024 Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer. Cancer Discov, 14(7):1324-55.
Zuo C, Baer JM, Knolhoff BL, Belle JI, Liu X, Alarcon De La Lastra A, Fu C, Hogg GD, Kingston NL, Breden MA, Dodhiawala PB, Zhou DC, Lander VE, James CA, Ding L, Lim KH, Fields RC, Hawkins WG, Weber JD, Zhao G, DeNardo DG. 2023 Stromal and therapy-induced macrophage proliferation promotes PDAC progression and susceptibility to innate immunotherapy. J Exp Med, 220(6):e20212062.
Herzog BH, Baer JM, Borcherding N, Kingston NL, Belle JI, Knolhoff BL, Hogg GD, Ahmad F, Kang LI, Petrone J, Lin CY, Govindan R, DeNardo DG. 2023 Tumor-associated fibrosis impairs immune surveillance and response to immune checkpoint blockade in non-small cell lung cancer. Sci Transl Med, 15(699):eadh8005.
Lander VE, Belle JI, Kingston NL, Herndon JM, Hogg GD, Liu X, Kang LI, Knolhoff BL, Bogner SJ, Baer JM, Zuo C, Borcherding NC, Lander DP, Mpoy C, Scott J, Zahner M, Rogers BE, Schwarz JK, Kim H, DeNardo DG. 2022 Stromal reprogramming by FAK inhibition overcomes radiation resistance to allow for immune priming and response to checkpoint blockade. Cancer Discov, 12(12):2774-99.
Su X, Xu Y, Fox GC, Xiang J, Kwakwa KA, Davis JL, Belle JI, Lee WC, Wong WH, Fontana F, Hernandez-Aya LF, Kobayashi T, Tomasson HM, Su J, Bakewell SJ, Stewart SA, Egbulefu C, Karmakar P, Meyer MA, Veis DJ, DeNardo DG, Lanza GM, Achilefu S, Weilbaecher KN. 2021 Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment. J Clin Invest, 131(20):e145296.
Ricci B, Tycksen E, Celik H, Belle JI, Fontana F, Civitelli R, Faccio R. 2020 Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics. Elife, 9():e54659.