Targeting TGFβR2‐mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer
Open accessAbstract
TGFβ is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGFβ signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGFβ has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGFβR2 reduces IL‐6 production from cancer‐associated fibroblasts, resulting in a reduction of STAT3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell‐specific deficiency in canonical TGFβ signaling via loss of TGFβR2. We demonstrate that in PDA that harbors epithelial loss of TGFβR2, inhibition of TGFβ signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGFβ blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.
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It may also explain the expression and functions of EMT transcription factors in a fraction of stromal fibroblasts.
“It may also explain the expression and functions of EMT transcription factors in a fraction of stromal fibroblasts253,254.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [253]
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Background<i>STAT3</i> Plays a Critical Role in <i>KRAS</i> -Induced Pancreatic Tumorigenesis
Corcoran, R. B., Contino, G., Deshpande, V., Tzatsos, A., Conrad, C., Benes, C. H., Levy, D. E., Settleman, J., Engelman, J. A., & Bardeesy, N. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0908 · Cited by 413 · cited 2× · see citing works
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BackgroundFibroblasts Mobilize Tumor Cell Glycogen to Promote Proliferation and Metastasis
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BackgroundSelf-citationPancreatic cancer–associated stroma production
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BackgroundSelf-citationLIF Mediates Proinvasive Activation of Stromal Fibroblasts in Cancer
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“Multiple studies indicate that TGFb can directly inhibit NK cell activation (Rook et al, 1986; Zhong et al, 2010; Rouce et al, 2016; Viel et al, 2016).”
BackgroundLoss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance
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“Importantly, these xenografts were grown in NOD SCID mice, which lack cells of the adaptive immune system (Hudson et al, 1998).”
BackgroundTGF-β and αvβ6 Integrin Act in a Common Pathway to Suppress Pancreatic Cancer Progression
Hezel, A. F., Deshpande, V., Zimmerman, S. M., Contino, G., Alagesan, B., O’Dell, M. R., Rivera, L. B., Harper, J. W., Lonning, S. M., Brekken, R. A., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-0634 · Cited by 99 · cited 3× · see citing works
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“Moreover, induction of IL-6 and LIF by TGFb has been reported in different types of fibroblasts including CAFs in other cancers (Eickelberg et al, 1999; Albrengues et al, 2014; Shintani et al, 2016; Dufour et al, 2018; Curtis et al, 2019).”
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“Production of viral supernatants and infection of target cells have been described previously (Huang et al, 2016).”
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“In contrast, TGFb also modulates many microenvironmental events that cancer cells exploit, including CAF activity and immune regulation (Ostapoff et al, 2014; Principe et al, 2016).”
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“5a).145,146 In turn, CAFs autocrine TGFβ can serve as an attractant to recruit more fibroblasts into the TME around the tumor invasion front and promote metastasis.147,148 CAFs surround and throughout the tumor often restrict the accessibility of anti-cancer drugs to tumor cells since the dense CAFs with stiff surroun…”
BackgroundOvercoming TGFβ-mediated immune evasion in cancer
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“demonstrated that TGF-β-induced secretion of IL-6 from CAFs inhibited NK cell activity in in vitro and in vivo murine PDAC models [142].”
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“Interestingly, inhibiting TGF-β receptor can reduce IL-6 production in CAFs, leading to decreased STAT3 activation in tumors and reversed immunosuppression in mouse models (Huang et al., 2019).”
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“Direct inhibition of TGF-β, blocking its downstream signaling and antagonizing its receptor can reverse the activated CAFs [167–169].”
BackgroundSingle-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches
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Self-citationThe role of TGF-β in the tumor microenvironment of pancreatic cancer
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“When cancer occurs, TGF-b is mainly secreted by tumor cells, stromal cells, and macrophages in the tumor infiltration zone in TME.28e30 In PC, Treg cells are the key source of TGF-b,31 and Schwann cells are also an important source of TGF-b.32 TGF-b has a bi-directional role in PC.”
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“CAFderived IL-6 is a major contributor to immune evasion in PDAC [98].”
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“However, given the cytostatic effect of TGFβ on epithelial cells, the therapeutic benefit of directly targeting TGFβ might depend on the mutational status of TGFβ receptors [117].”
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Advances in Immunotherapy and the TGF-β Resistance Pathway in Metastatic Bladder Cancer
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“The activated TGF-β signaling in fibroblasts can also promote cell survival and protect against cell death (Figure 1), playing a role in cancer progression [49,50].”
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“IL-1 and TGF-b have also been identified as ligands to promote CAF heterogeneity (125, 138).”
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“Recently, the complex heterogeneity of CAFs has been revealed by other studies, indicating the existence of CAF subpopulations equipped with pro-and antitumorigenic qualities (19 – 21 , 29 ).”
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Genetics, Genomics and Emerging Molecular Therapies of Pancreatic Cancer
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“…continues to be produced by which EMT (Feng et al. 2022), cell metastasis (Yoon et al. 2021), angiogenesis(Chen et al. 2021), and immune escape (Huang et al. 2019) are induced through increasing neovascularization and extracellular matrix production, upregulating peritumoral proteases, or…”
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“However, TGF-β signaling is multifaceted and cell type specific in PDAC [42].”
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“While targeting TGF β R2 -mutant tumors exposes vulnerabilities to stromal TGF-β blockade in pancreatic cancer, canonical TGF-β signaling suppresses epithelial pancreatic cancer (PDA) cell proliferation, and as a result, inhibiting TGF-β has not been successful [11].”
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“4B ), consistent with our previous results using 2G8, a mAb against mouse TGF β R2 , as well as clinical trials of TGF β inhibitors in unselected cohorts of patients with epithelial cancers (10, 13).”
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Toward personalized TGFβ inhibition for pancreatic cancer
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“It has been reported that IL6 is regulated by TGF-β signaling [14,15].”
Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy
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“This is eloquently demonstrated in themurine pancreatic BMFA3 tumormodel, where treatment with an anti-TGF-βR2 antibody significantly slowed the growth of Tgfbr-mutant tumors but increased the growth of Tgfbrwt tumors (56).”
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Immunotherapy‐induced reprogramming of cancer‐associated fibroblasts can promote tumor progression
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“In pancreatic ductal adenocarcinoma, IL-6 secreted by iCAFs is a major contributor to tumorigenesis and immune evasion (Huang et al., 2019).”
STAT signaling pathways in immune cells and their associated mechanisms in cancer pathogenesis
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“40,41 Elevated STAT3 activity in CAFs also affects other immune cells.”
DOLPHIN advances single-cell transcriptomics beyond gene level by leveraging exon and junction reads
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“…in PDAC 56,57 ; TGFBR2 , a key component of TGF-beta signaling, which plays a dual role in tumor suppression and progression in pancreatic cancer 58,59 ; and ATM , a DNA damage response kinase frequently mutated in PDAC, where its loss impairs double-strand break repair and confers increased…”
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“4 anti-tumor adaptive immunity, and promote immune evasion in PDAC (11, 13, 16, 17).”
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“Compared with gemcitabine, galunisertib is the first oral drug to inhibit TGF-β , and it significantly improves the outcome of patients (Huang H. et al., 2019; Melisi et al., 2018).”
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It Takes a Village to Overcome KRAS Dependence in Pancreatic Cancer
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Self-citationecDNA-driven oncogene super-expressors shape immunoevasive tumor microenvironmentPreprint
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Self-citationThe Tumor Microenvironment in Pancreatic Cancer and Challenges to Immunotherapy
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“Alterations in TGFBR2 have been associated with reduced survival and poorer postoperative outcomes in PDAC patients (Huang et al. 2019 ).”
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- Authors
- Huang, H., Zhang, Y., Gallegos, V., Sorrelle, N., Zaid, M. M., Toombs, J., Du, W., Wright, S., Hagopian, M., Wang, Z., Hosein, A. N., Sathe, A. A., Xing, C., Koay, E. J., Driscoll, K. E., & Brekken, R. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at El Paso (US)
- The University of Texas MD Anderson Cancer Center (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Brekken, Rolf A
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2019-10-14
- Volume
- 11
- Issue
- 11
- Pages
- e10515-e10515
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC6835203
- OpenAlex
- W2980314475
- Cited by
- 87
- References
- 54
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 16 · 2023: 14 · 2022: 14 · 2021: 14 · 2020: 8 · 2019: 1
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Eli Lilly & Company (SRA5200886401)
- HHS|National Institutes of Health (CA192381, CA210181)
- American Heart Association (19PRE34380436)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- TGFBR2, pancreatic ductal adenocarcinoma, TGF-beta signaling, cancer-associated fibroblasts, interleukin-6, STAT3 activation, tumor immunosuppression, tumor microenvironment, targeted therapy
- MeSH terms
- Cardiomegaly, Humans, Pancreatic Neoplasms, Signal Transduction, Transforming Growth Factor beta, Carcinoma, Pancreatic Ductal
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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