VIEWS

FEBRUARY 2019 CANCER DISCOVERY | 173

1 Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 2 The University of Texas, The Graduate School of Biomedical Sciences, Houston , Texas. Corresponding Author: Paul J. Chiao, Department of Molecular and Cel-lular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1030; Fax: 713-7940-4830; E-mail: pjchiao@mdanderson.org doi: 10.1158/2159-8290.CD-18-1460 ©2019 American Association for Cancer Research.

IN THE SPOTLIGHT

Two Birds with One Stone: Therapeutic Targeting of IL1` Signaling Pathways in Pancreatic Ductal Adenocarcinoma and the Cancer-Associated Fibroblasts Jianhua Ling 1 and Paul J. Chiao 1 , 2

Summary: In this issue of Cancer Discovery , Biffi and colleagues report that IL1 signaling cascades resulted in JAK/STAT activation and promoted an infl ammatory cancer-associated fi broblast (iCAF) state, which contributed to the establishment of distinct fi broblast niches in the pancreatic ductal adenocarcinoma (PDAC) microenvironment to support the growth of PDAC cells. Furthermore, the investigators demonstrated that TGFβ signaling inhibited IL1R1 expression, antagonized IL1α responses, and promoted differentiation of CAFs into myofi broblasts; thus, IL1α signaling is an important therapeutic target for both PDAC cells and the iCAFs in the tumor microenvironment.

See related article by Biffi et al., p. 282 (8).

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the United States, with 55,440 new cases estimated in 2018 by the American Can-cer Society, and the 5-year survival rate has remained at 6% for the past 50 years. PDAC is projected to surpass breast, prostate, and colorectal cancers as the second leading cause of cancer-related deaths by 2030 ( 1 ). Approximately 80% of patients with PDAC present with locally advanced or meta-static therapy-resistant disease at the time of diagnosis, and the median survival after diagnosis is 6 months. Despite major advances, current chemotherapy and radiotherapy regimens remain largely ineffective, as most PDACs are resist-ant to standard therapy. Hence, a better understanding of the molecular basis of PDAC inception and development is crucial to identifying effective therapies to improve patient survival, which is currently one of the greatest challenges in pancreatic cancer research.

Genetic and molecular profi les of PDAC are emerging and include some of the following major alterations ( 2 ). Mutational KRAS activation is an early event in pancre-atic carcinogenesis and is detected in 80% to 95% of PDAC cases, whereas inactivation of SMAD4 and TP53 tumor sup-pressor genes is identifi ed in approximately 50% of PDAC cases. Additionally, constitutive NF-κB activation is found in nearly 70% of PDAC, most PDAC cell lines, and in many other tumor types ( 3 ). IL1 includes two major agonistic pleiotropic ligands, IL1α and IL1β. IL1β is a secreted active ligand, whereas IL1α is active in the cell membrane–bound form. IL1α is overexpressed in many types of cancers and

plays a key role in tumorigenesis and metastasis ( 4 ). Knock-down and knockout of IL1α or IKK2 inhibit NF-κB activa-tion and tumorigenesis in PDAC cells. NF-κB activation in RAS-transformed cells is induced by IκB kinase (IKK) and by autocrine IL1α/p62 feed-forward pathways ( 5 ). These results demonstrate that NF-κB activation by IL1α is required for mutant KRAS–induced tumorigenesis. Activated NF-κB inte-grates proinfl ammatory signals and orchestrates antiapop-totic responses; thus, NF-κB signaling has been implicated as a hallmark of cancer development and a potential thera-peutic target ( 6 ). Previously, Ohlund and colleagues ( 7 ) dem-onstrated that pancreatic stellate cells (PSC) in the tumor microenvironment differentiated into two subtypes of cancer-associated fi broblasts (CAF): infl ammatory CAFs (iCAF) and myofi boblast CAFs (myCAF). The current fi nding of Biffi and colleagues shows that inhibition of NF-κB activation impaired the ability of tumor organoid–conditioned media to induce infl ammatory CAF marker genes in PSCs, which suggests that NF-κB activation is required for the formation of iCAFs ( 8 ). They also demonstrate that IL1α-induced autocrine stimulation of LIF in PSCs activates JAK/STAT signaling and enhances iCAF formation. Therefore, their new fi ndings pro-vide an important mechanism of the IL1α signaling cascade in inducing iCAF in PDAC development and strengthen the rationale for therapeutic targeting of IL1α signaling in both PDAC and the tumor microenvironment ( Fig. 1 ).

The SMAD4 tumor suppressor gene encodes a transcrip-tion factor that is a central effector of TGFβ and is fre-quently deleted or mutated in PDAC, resulting in defective TGFβ signaling ( 9 ). The activated KRAS G12D allele with con-comitant haploinsuffi ciency of expression of SMAD4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms, which culminate in invasive ductal adenocarcinomas and evolve along a pro-gression scheme analogous to, but distinct from, the clas-sic PanIN-to-ductal adenocarcinoma sequence ( 10 ). In this report, Biffi and colleagues identifi ed that TGFβ signaling antagonized IL1α-induced JAK/STAT signaling in myCAFs. Furthermore, the results from Biffi and colleagues showed

Research. on August 26, 2020. © 2019 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

VIEWS

174 | CANCER DISCOVERY FEBRUARY 2019 www.aacrjournals.org

Figure 1.  The interaction of the IL1α and TGFβ paracrine pathways between PDAC cells and CAFs in the tumor microenvironment. Asterisk indicates mutant.

IL1α

IL1α

IL1α

Inhibition of IL1 signaling pathway

IL1α

IL1R

LIF

iCAF

ECM

PSCmyCAF

Pancreatic cancer cell

JAK/STAT

IL1RIL6CXCL1

Nucleus

Cytoplasm

Cytoplasm

Cytoplasm

Kras*IL1R

TAK1SMAD4

NF-κB

NF-κB

IL1R

TGFβ

TGFβR

αSMACol1α1CTGF

JAK/STAT

Antiapoptosis

Inflammation

Proliferation

Autocrine signaling

Para

crin

e signaling

Paracrine signaling

Paracrine signaling

Juxtacrine signaling

Para

crin

e si

gnal

ing

that the inhibition of the TGFβ or JAK/STAT pathway shifted iCAFs to myofibroblastic phenotype in vivo (ref. 8; Fig. 1). The authors demonstrated that activation of the NF-κB pathway was associated with the expression of various cytokines and chemokines in iCAFs, which may play a role in recruiting inflammatory cells into PDAC.

The combined mouse genetic and functional studies using organoid cultures have revealed that IL1 signaling cascades result in JAK/STAT activation and promote an inflammatory CAF state, facilitating the establishment of distinct fibroblast niches in the PDAC microenvironment to support PDAC development (Fig. 1). Moreover, in PDAC cells, loss or muta-tion of SMAD4, a common event in PDAC development, plays a key role in the progression of KRAS-initiated PDAC in the Pdx1-Cre; KrasG12D; Smad4L/L PDAC mouse model by enhanc-ing activation of the NF-κB signaling pathway, which in turn increases the expression of proinflammatory cytokines and chemokines that modulate the PDAC tumor microen-vironment. Thus, inactivation of TGFβ signaling intensified IL1α signaling cascades in PDAC cells. However, significant gaps still exist in our understanding of how such genetic alterations act accordingly to induce activation of NF-κB and JAK/STAT signaling for PDAC development and progression. This question has now been answered in part by the findings of Biffi and colleagues.

These new findings raise several important questions. (i) Can the IL1R signaling pathway be effectively inhibited by recombinant IL1RA, IL1R antibodies, and IL1R chemical inhibitors in patients? (ii) Can the tumorigenesis of PDAC cells be further reduced with a combination treatment with IL1 inhibitors and a chemotherapeutic agent? (iii) Is there an IL1α-independent pathway responsible for the develop-ment of PDAC-related inflammatory responses and iCAF? (iv) What is the expression profile of various NF-κB–depend-ent cytokines and chemokines in the epithelial cells express-ing mutant KRAS? (v) How is the cooperation between tumor cells and their inflammatory surroundings orches-trated? (vi) Do the high levels of cytokines and chemokines in the tumor microenvironment further amplify the NF-κB activation through the IL1α/p62 feed-forward mechanism in TGFβ-deficient cells to promote PDAC development? (vii) Is there an IL1α autocrine stimulatory pathway in myCAF cells?

The stroma consists of cellular components, predomi-nantly CAFs, immune cells, and a rich extracellular matrix (ECM), many of which closely interact with cancer cells to promote growth and metastasis. The activation of the auto-crine and paracrine oncogenic signaling pathways by stroma-derived growth factors and cytokines has been implicated in promoting tumor cell proliferation and metastasis, indicating

Research. on August 26, 2020. © 2019 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

VIEWS

FEBRUARY 2019 CANCER DISCOVERY | 175

that targeting tumor–stroma interactions is a promising strategy in the search for novel treatment modalities in human cancer. Comprehensive analysis of the PDAC genome and evaluation of the profiles of various signaling pathways are needed to identify potential therapeutic targets, such as IL1 and NF-κB pathways, in a large human PDAC sample. The findings by Biffi and colleagues have provided an enlight-ening understanding of PDAC heterogeneity, and this knowl-edge is important for developing therapeutic approaches that selectively target tumor-promoting CAFs. The discovery of the role of the IL1α signaling pathway in promoting iCAFs that function in CAFs of the tumor microenvironment may lead to the identification of novel and effective therapeutic targets. Thus, directly inhibiting the key cytokine signaling pathways in PDAC harboring SMAD4 deficiencies presents a promising application for targeted therapy. IL1-induced signaling cascades lead to JAK/STAT activation and promote an inflammatory CAF state, which suggests that there may be multiple possibilities in targeting these cells in vivo, such as the JAK/STAT and NF-κB signaling pathways for gener-ating inflammatory CAFs. Further, TGFβ antagonizes this process by downregulating IL1R1 expression and promoting differentiation into myofibroblasts. These results provide a mechanism by which Smad4 loss and IL1 overexpression are altered in PDAC cells. Such molecular hallmarks cooperate to accelerate pancreatic cancer development by enhancing NF-κB activation and upregulating downstream cytokine genes, thus promoting a protumorigenic and metastatic microenvironment. Importantly, the findings by Biffi and colleagues offer unique therapeutic opportunities through the development of drugs that specifically target and inhibit well-defined inflammatory pathways in both PDAC cells and the iCAFs (Fig. 1).

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

AcknowledgmentsP.J. Chiao is supported by a grant from the NIH/NCI (CA207031).

We thank Dr. Huaiqiang Ju for help with graphics.

Published online February 8, 2019.

REFERENCES 1. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM,

Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21.

2. Ying H, Dey P, Yao W, Kimmelman AC, Draetta GF, Maitra A, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev 2016;30:355–85.

3. Wang W, Abbruzzese JL, Evans DB, Chiao PJ. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene 1999;18:4554–63.

4. Di Paolo NC, Shayakhmetov DM. Interleukin 1alpha and the inflam-matory process. Nat Immunol 2016;17:906–13.

5. Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, et al. KrasG12D-induced IKK2/beta/NF-kappaB activation by IL-1alpha and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell 2012;21:105–20.

6. Zhuang Z, Ju HQ, Aguilar M, Gocho T, Li H, Iida T, et al. IL1 recep-tor antagonist inhibits pancreatic cancer growth by abrogating NF-kappaB activation. Clin Cancer Res 2016;22:1432–44.

7. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med 2017;214:579–96.

8. Biffi G, Oni TE, Spielman B, Hao Y, Elyada E, Park Y, et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov 2019;9:282–301.

9. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996;271:350–3.

10. Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 2007;11:229–43.

Research. on August 26, 2020. © 2019 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

2019;9:173-175. Cancer Discov   Jianhua Ling and Paul J. Chiao  the Cancer-Associated FibroblastsSignaling Pathways in Pancreatic Ductal Adenocarcinoma and

αTwo Birds with One Stone: Therapeutic Targeting of IL1

  Updated version

  http://cancerdiscovery.aacrjournals.org/content/9/2/173

Access the most recent version of this article at:

   

   

  Cited articles

  http://cancerdiscovery.aacrjournals.org/content/9/2/173.full#ref-list-1

This article cites 10 articles, 6 of which you can access for free at:

  Citing articles

  http://cancerdiscovery.aacrjournals.org/content/9/2/173.full#related-urls

This article has been cited by 1 HighWire-hosted articles. Access the articles at:

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  SubscriptionsReprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerdiscovery.aacrjournals.org/content/9/2/173To request permission to re-use all or part of this article, use this link

Research. on August 26, 2020. © 2019 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from