Areas of Research
Radiation Protection
Pancreatic cancer is one of the most frustrating and heartbreaking cancers for oncologists, scientists, and most of all patients. This is due to the fact that unless surgery can be performed to remove the tumor before it metastasizes it is considered incurable. The normal treatment for patients with locally advanced pancreatic cancer is 3-6 months of chemotherapy, usually FOLFIRINOX or gemcitabine and nab-paclitaxel. If the tumor responds by shrinking enough for surgery, most agree that operation to remove the tumor should be done. What happens though if critical structures or blood vessels are still nearby? Unfortunately, the option to continue chemotherapy or treat with some radiation are not currently curative, but most likely life prolonging.
The Taniguchi Lab wants to show that there are other options than standard radiation. For patients with tumors located in the body and tail of the pancreas dose-escalated radiotherapy can sometimes be used in place of surgery. Unfortunately, these patients are not the majority. The image to the left depicts our goal. The purple pancreas and tumor show the proximity of the intestines which currently limits our ability to treat the tumor with ablative radiation due to the sensitivity of the intestines. We reason that a selective radioprotector is needed, the green in the image gives us an artistic representation of protection.
The Taniguchi lab is focusing on understanding the mechanisms of radiation protection. We developed 3 approaches to protecting the intestines during radiation treatments, 1. EGLN inhibition (FG-4592); 2. oral amifostine; and 3. Avasopasem (superoxide dismutate mimic). All three are either in clinical trials or en route to a clinical trial. Exposure to this process is useful for any scientists wishing to understand the challenges and excitement of bringing a therapy from the lab to the patient.
Our key projects to better understand the mechanisms or radioprotection are:
1. Identification of the stem cells being protected by the radioprotector listed above. We are investigating the evidence suggesting that FG-4592 protects some stem cell subtypes, using human enteroids with single cell RNA seq technology.
2. In 2021 we published our findings of Wnt5a being a downstream mediator of HIF2 radioprotection. Further sequencing data provided several other possible targets with even stronger effects, leading us to ask, what are the other downstream mediators of HIF2 radioprotection?
Selected publications related to this project:
Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer.
Fujimoto TN, Colbert LE, Huang Y, Molkentine JM, Deorukhkar A, Baseler L, de la Cruz Bonilla M, Yu M, Lin D, Gupta S, Cabeceiras PK, Kingsley CV, Tailor RC, Sawakuchi GO, Koay EJ, Piwnica-Worms H, Maitra A, Taniguchi CM.
Cancer Res. 2019 May 1;79(9):2327-2338. doi: 10.1158/0008-5472.CAN-18-1785. PMID: 31043430.
Enteral Activation of WR-2721 Mediates Radioprotection and Improved Survival from Lethal Fractionated Radiation.
Molkentine JM, Fujimoto TN, Horvath TD, Grossberg AJ, Garcia CJG, Deorukhkar A, de la Cruz Bonilla M, Lin D, Samuel ELG, Chan WK, Lorenzi PL, Piwnica-Worms H, Dantzer R, Tour JM, Mason KA, Taniguchi CM.
Sci Rep. 2019 Feb 13;9(1):1949. doi: 10.1038/s41598-018-37147-9. PMID: 30760738.
HIF2 Regulates Intestinal Wnt5a Expression.
García García CJ, Acevedo Diaz AC, Kumari N, Govindaraju S, de la Cruz Bonilla M, San Lucas FA, Nguyen ND, Jiménez Sacarello I, Piwnica-Worms H, Maitra A, Taniguchi CM.
Front Oncol. 2021 Nov 25;11:769385. doi: 10.3389/fonc.2021.769385. PMID: 34900719.
PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2.
Taniguchi CM, Miao YR, Diep AN, Wu C, Rankin EB, Atwood TF, Xing L, Giaccia AJ.
Sci Transl Med. 2014 May 14;6(236):236ra64. doi: 10.1126/scitranslmed.3008523. PMID: 24828078.
Hypoxia and Tumor Microevironment
Pancreatic ductal adenocarcinoma (PDAC) has a fibrotic and desmoplastic stroma, which is essentially a scar embedded with cancer cells. Unlike healthy scars, the fibrotic pancreatic tumor grows thick and dense to the point where oxygen has trouble diffusing within it. This has been confirmed by direct measurement of oxygen in patient tumors during surgery (Koong , et al IJORBP 2000). In addition to low oxygen levels, the high intratumoral pressure from the stroma reduces the delivery therapeutic drugs. The initial strategy to counteract the stroma was to reduce the physical barrier caused by this desmoplasia to allow more chemotherapy to reach the cancer. Unfortunately, after promising Phase II clinical trials (Hingorani, et al. JCO 2018), multiple Phase III studies failed to meet survival endpoints. Thus, our lab pivoted from this initial strategy of stromal destruction to focus on functional inhibition of the stroma.
The Taniguchi lab believes that hypoxia plays a critical role in the cellular homeostasis of the tumor microenvironment in PDAC. Specifically, the low oxygen environment changes the way that cells communicate. We collaborated with the Kirsch Lab (soon to be PMH in May 2023) and the Saur lab in Munich to develop a powerful dual recombinase system. With this approach we found that hypoxic cancer-associated fibroblasts (CAFs) may transmit chemical signals to nearby immune cells to reduce their function. Specifically, we published in Gastroenterology (May 2022) where we show that hypoxia signaling within fibroblasts promote the immunosuppressive M2 polarization of macrophages. This in turn suppressed anti-tumor T cell responses, providing favorable tumor growth conditions. Further investigation allowed us to identify that the effect was HIF2 dependent, which could be reversed with a HIF2 inhibitor call PT2399, an experimental version of the FDA-approved belzutifan used in VHL-mutant renal cell carcinoma. We are currently in active discussions to repurpose belzutifan for use in pancreatic cancer as a way to improve immunotherapy responses.
We are currently focused on identifying what paracrine factor secreted from CAFs is inducing M2 polarization in macrophages using mass spectrometry-based approaches with our collaborator Marian Kalocsay. Using both pre-clinical and in vitro systems we aim to determine the role of hypoxia in every cell type within the PDAC microenvironment. The goal is to better understand hypoxia’s role and identify weak points that could potentially be druggable. We plan to use this approach to broadly elucidate hypoxia-dependent cell-cell communication within the pancreatic cancer microenvironment.
Our key projects currently being investigated in the lab include:
1. Identifying the HIF2-dependent paracrine factor mediating the immunosuppressive crosstalk in the microenvironment.
2. Translating belzutifan (Merck, HIF2 ihibitor) for use in pancreatic cancer
3. Understanding the effects of hypoxia signaling in cancer associated fibroblasts (CAFs) on T cell activation
Selected publications related to this project:
Stromal HIF2 Regulates Immune Suppression in the Pancreatic Cancer Microenvironment.
Garcia Garcia CJ, Huang Y, Fuentes NR, Turner MC, Monberg ME, Lin D, Nguyen ND, Fujimoto TN, Zhao J, Lee JJ, Bernard V, Yu M, Delahoussaye AM, Jimenez Sacarello I, Caggiano EG, Phan JL, Deorukhkar A, Molkentine JM, Saur D, Maitra A, Taniguchi CM.
Gastroenterology. 2022 Jun;162(7):2018-2031. doi: 10.1053/j.gastro.2022.02.024. Epub 2022 Feb 22. PMID: 35216965.
Resolving the HIF paradox in pancreatic cancer.
Fuentes NR, Phan J, Huang Y, Lin D, Taniguchi CM.
Cancer Lett. 2020 Oct 1;489:50-55. doi: 10.1016/j.canlet.2020.05.033. Epub 2020 Jun 5. PMID: 32512024.
Hypoxia inducible factor (HIF) in the tumor microenvironment: friend or foe?
Huang Y, Lin D, Taniguchi CM.
Sci China Life Sci. 2017 Oct;60(10):1114-1124. doi: 10.1007/s11427-017-9178-y. Epub 2017 Oct 13. PMID: 29039125.
PHD inhibition mitigates and protects against radiation-induced gastrointestinal toxicity via HIF2.
Taniguchi CM, Miao YR, Diep AN, Wu C, Rankin EB, Atwood TF, Xing L, Giaccia AJ. Sci Transl Med. 2014 May 14;6(236):236ra64. doi: 10.1126/scitranslmed.3008523. PMID: 24828078.
Mitochondria and the Tumor Microenvironment
Throughout our school years the one thing everyone will remember from biology class is “Mitochondria are the powerhouse of the cell”. Nearly every cell in our body requires healthy active mitochondria to function properly, and cancers are no exception to this. But this creates a problem of how to target mitochondria in cancer cells without hurting normal tissues that also use mitochondria.
The Taniguchi Lab has found a possible solution to this problem in pancreatic cancer. When you look at the mitochondria of pancreatic cancer cells, they tend to be 2-10x smaller than mitochondria in normal cells. In the colorized image of Transmission Electron Microscopy (TEM) above the mitochondria are the purple “circles”. Mitochondria this small would typically be damaged or nonfunctional, but in pancreatic cancer cells, they are very active.
We wondered if this small size of cancer mitochondria could allow us to target pancreatic cancer therapeutically. In our JCI Insight paper (2019) we learned that fusing these small mitochondria together to make larger organelles independently regulates metabolism and metastasis in pancreatic cancer. We used genetic and pharmacologic means to induce mitochondrial fusion and are pursuing further ways to optimize this pathway as a therapeutic target.
Some questions we are currently working on answering:
1. Why does pancreatic cancer use these punctate mitochondria so efficiently? Is it helpful with inter-cellular signaling or all for faster cell division?
2. Could we use mitochondrial fusion as a possible therapy option in cancer?
3. Are there other pathways of mitochondrial dynamics that we can use against pancreatic cancer?
4. What is the role of mitochondrial dynamics in the stromal cells and tumor cells in pancreatic cancer?
Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.
Yu M, Nguyen ND, Huang Y, Lin D, Fujimoto TN, Molkentine JM, Deorukhkar A, Kang Y, San Lucas FA, Fernandes CJ, Koay EJ, Gupta S, Ying H, Koong AC, Herman JM, Fleming JB, Maitra A, Taniguchi CM.
JCI Insight. 2019 Jul 23;5(16):e126915. doi: 10.1172/jci.insight.126915. PMID: 31335325.
Comparative Untargeted Metabolomic Profiling of Induced Mitochondrial Fusion in Pancreatic Cancer.
Nguyen ND, Yu M, Reddy VY, Acevedo-Diaz AC, Mesarick EC, Abi Jaoude J, Yuan M, Asara JM, Taniguchi CM.
Metabolites. 2021 Sep 15;11(9):627. doi: 10.3390/metabo11090627. PMID: 34564443.